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Facial deformities require precise reconstruction of the appearance and function of the original tissue. The current standard of care—the use of bone harvested from another region in the body—has major limitations, including pain and comorbidities associated with surgery. We have engineered one of the most geometrically complex facial bones by using autologous stromal/stem cells, native bovine bone matrix, and a perfusion bioreactor for the growth and transport of living grafts, without bone morphogenetic proteins. The ramus-condyle unit, the most eminent load-bearing bone in the skull, was reconstructed using an image-guided personalized approach in skeletally mature Yucatán minipigs (human-scale preclinical model). We used clinically approved decellularized bovine trabecular bone as a scaffolding material and crafted it into an anatomically correct shape using image-guided micromilling to fit the defect. Autologous adipose-derived stromal/stem cells were seeded into the scaffold and cultured in perfusion for 3 weeks in a specialized bioreactor to form immature bone tissue. Six months after implantation, the engineered grafts maintained their anatomical structure, integrated with native tissues, and generated greater volume of new bone and greater vascular infiltration than either nonseeded anatomical scaffolds or untreated defects. This translational study demonstrates feasibility of facial bone reconstruction using autologous, anatomically shaped, living grafts formed in vitro, and presents a platform for personalized bone tissue engineering.

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The efforts to grow mechanically functional cartilage from human mesenchymal stem cells have not been successful. We report that clinically sized pieces of human cartilage with physiologic stratification and biomechanics can be grown in vitro by recapitulating some aspects of the developmental process of mesenchymal condensation. By exposure to transforming growth factor-ß, mesenchymal stem cells were induced to condense into cellular bodies, undergo chondrogenic differentiation, and form cartilagenous tissue, in a process designed to mimic mesenchymal condensation leading into chondrogenesis. We discovered that the condensed mesenchymal cell bodies (CMBs) formed in vitro set an outer boundary after 5 d of culture, as indicated by the expression of mesenchymal condensation genes and deposition of tenascin. Before setting of boundaries, the CMBs could be fused into homogenous cellular aggregates giving rise to well-differentiated and mechanically functional cartilage. We used the mesenchymal condensation and fusion of CMBs to grow centimeter-sized, anatomically shaped pieces of human articular cartilage over 5 wk of culture. For the first time to our knowledge biomechanical properties of cartilage derived from human mesenchymal cells were comparable to native cartilage, with the Young’s modulus of >800 kPa and equilibrium friction coeffcient of <0.3. We also demonstrate that CMBs have capability to form mechanically strong cartilage–cartilage interface in an in vitro cartilage defect model. The CMBs, which acted as “lego-like” blocks of neocartilage, were capable of assembling into human cartilage with physiologic-like structure and mechanical properties.        

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Pancreatic islet implantation has been recently shown to be an efficient method of treatment for type 1 diabetes. However, limited availability of donor islets reduces its use. Bone morrow would provide potentially unlimited source of stem cells for generation of insulin-producing cells. This study was performed to evaluate the influence of extracellular matrix proteins like collagen, laminin, and vitronectin on bone marrow mesenchymal stem cells (BM-MSCs) transdifferentiation into islet-like cells (ILCs) in vitro. To our knowledge, this is the first report evaluating the importance of vitronectin in transdifferentiation of BM-MSCs into ILCs. Rat BM-MSCs were induced to ILCs using four-step protocol on plates coated with collagen type IV, laminin type I and vitronectin type I. Quantitative real-time PCR was performed to detect gene expression related to pancreatic ß cell development. The induced cells expressed islet-related genes including: neurogenin 3, neurogenic differentiation 1, paired box 4, NK homeobox factor 6.1, glucagon, insulin 1 and insulin 2. Laminin but not collagen type IV or vitronectin enhanced expression of insulin and promoted formation of islet-like structures in monolayer culture. Laminin triggered transdifferentiation of BM-MSCs into ILCs.

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Introduction: This systematic review is designed to assess the safety and efficacy of mesenchymal stromal/stem cells (MSCs) in the treatment of disc degeneration.

Methods: The researchers conducted a systematic review of peer-reviewed comparative controlled studies to assess the safety and efficacy of MSCs compared to no treatment/saline in animals and human subjects. A total of 24 animal studies met the inclusion criteria, 6 of which reported at least partial randomization of treatment. In these animal studies, 862 discs were treated with MSC injection, and 1,603 discs served as controls. The studies included both small animals (mouse, rat, and rabbit) and larger animals (sheep, dogs, and minipigs). None of the human trials met the inclusion criteria.

Results: Overall, MSC injection significantly inhibited disc degeneration, defined as restoration of disc height index similar to that of control discs and increased expression of proteoglycan or extracellular matrix genes. The majority of studies used bone marrow as the source of MSCs, but efficacy also was demonstrated in studies involving MSCs derived from synovial and adipose tissues. Bone-marrow-derived MSCs demonstrated superior quality of repair compared with other non-MSC treatments (eg, articular chondrocytes and mechanical distraction devices). A greater degree of degeneration was linked to greater efficacy of MSC injection.

The overall complication rate was 2.7%, and complications were only found in rabbit studies. These complications included osteophyte formation anterolaterally to the disc space, which was hypothesized to result from leakage of the MSCs.

Conclusion: MSCs were found to be safe and effective in animal models of disc degeneration. MSC injection increased disc space height in the majority of animal models evaluated in this review. The authors called for randomized clinical trials in humans.

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Functional tissue engineering of connective tissues such as the anterior cruciate ligament (ACL) remains a significant clinical challenge, largely due to the need for mechanically competent scaffold systems for grafting, as well as a reliable cell source for tissue formation. We have designed an aligned, polylactide-co-glycolide (PLGA) nanofiber-based scaffold with physiologically relevant mechanical properties for ligament regeneration. The objective of this study is to identify optimal tissue engineering strategies for fibroblastic induction of human mesenchymal stem cells (hMSC), testing the hypothesis that basic fibroblast growth factor (bFGF) priming coupled with tensile loading will enhance hMSC-mediated ligament regeneration. It was observed that compared to the unloaded, as well as growth factor-primed but unloaded controls, bFGF stimulation followed by physiologically relevant tensile loading enhanced hMSC proliferation, collagen production and subsequent differentiation into ligament fibroblast-like cells, upregulating the expression of types I and III collagen, as well as tenasin-C and tenomodulin. The results of this study suggest that bFGF priming increases cell proliferation, while mechanical stimulation of the hMSCs on the aligned nanofiber scaffold promotes fibroblastic induction of these cells. In addition to demonstrating the potential of nanofiber scaffolds for hMSC-mediated functional ligament tissue engineering, this study yields new insights into the interactive effects of chemical and mechanical stimuli on stem cell differentiation.

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OBJECTIVE:

The aim of this study was to determine if mesenchymal stem cells (MSCs) could be obtained from mandible marrow aspirates.

STUDY DESIGN:

In 5 patients, 10 mL marrow aspirates were obtained from both the mandible and the iliac crest. Second passage MSCs were characterized by fluorescence-activated cell sorting (FACS) analysis using MSC-specific cell surface marker, and fifth-passage cells were differentiated into 3 mesenchymal tissues in vitro.

RESULTS:

Average total cell yields of MSCs were 2.8 ± 1.8 × 10(5) per 10 mL marrow aspirates from the mandible. Immunophenotypes of MSCs isolated from the mandible and iliac crest were highly similar, as indicated by FACS analysis. Differentiation into mesodermal cell types, such as osteocytes, chondrocytes, and adipocytes, was successfully achieved in all MSC isolates from all aspirates.

The MSCs can be isolated from the mandibular aspirates, providing an alternative accessible source of MSCs for the treatment of future dental and craniomaxillofacial diseases.

Int J Oral Maxillofac Implants. 2011 Jan-Feb;26(1):123-31.

Gonshor A, McAllister BS, Wallace SS, Prasad H.

Faculty of Dentistry, McGill University, Montreal, Quebec, Canada. [email protected]

J Craniofac Surg. 2011 Mar;22(2):438-42.

Nishino Y, Ebisawa K, Yamada Y, Okabe K, Kamei Y, Ueda M.

From the Departments of *Oral and Maxillofacial Surgery and †Plastic and Reconstructive Surgery, Nagoya University Graduate School of Medicine; and ‡Center for Genetic and Regenerative Medicine, Nagoya University School of Medicine, Nagoya, Japan.

J Tissue Eng Regen Med. 2011 Apr;5(4):e1-e16. doi: 10.1002/term.369. Epub 2010 Dec 30.

Sun HH, Jin T, Yu Q, Chen FM.

Department of Operative Dentistry and Endodontics, School of Stomatology, Fourth Military Medical University, Xi'an 710032, Shaanxi, People's Republic of China.

Abstract

by Wynand van der Merwe

Lead researchers Jennifer L. West, PhD of  Rice University and Mary Dickenson, PhD of Baylor College of Medicine have developed a method to grow capillaries and blood vessels – a key element in growing tissue and organs for transplantation.  This breakthrough will advance stem cell based regeneration of tissue and organs by enabling researchers and doctors to grow thicker and more complex cellular structures.

The researchers made use of PEG (Polyethylene Glycerol), which is a non-toxic plastic, to form a base for cells to grow and then form blood vessels. Not only can they grow cells, but they can control the growth and movement of cells with the help of a process called “Two-Photon Lithography”.

“Two-Photon Lithography” is an ultra sensitive way of using light to control the movement and growth of cells which enabled the researchers to direct the growth of the cells in predetermined patterns, which for example could be the pattern of  the blood supply in a kidney.  Read more

In an earlier but related study, researchers at MIT found a way to induce cells to form tube like structures which can be used as blood vessels. EPC (Endothelial Progenitor cells) are grown on a patterned surface, that guide these cells to grow into a specific shape or size the scientists want it to grow in. According to Christopher Bettinger, PhD, this then takes the guess work out of what they are actually growing.  Read more

Success is already reported with the integration of these newly formed blood vessels within animal tissue. If a normal blood flow in these grown capillaries is established in human tissue, it could be transplanted into human organs such as the kidneys, liver, heart or any other tissue that requires vascularization.

By Doctor Dharmini Pathmanathan, DMD, PhD

The metal and plastic parts used in 581,000 knee replacement procedures performed per year may soon take up permanent residence in medical museums. Researchers, including Dr. Jeremy Mao, Director of the Tissue Engineering and Regenerative Medicine Laboratory at Columbia University and also Chief Scientific Advisor to StemSave, are leading the way to the virtual extinction of mechanical parts constructed for joint replacements and instead are focusing on biological counterparts constructed from the patient’s own stem cells.  According to Dr. James Cook, Professor at the University of Missouri, the biological products would last longer, be more flexible and give the patient a better quality of life.” Essentially the goal is to use autologous (the patient’s own stem cells) to generate cartilage for joint replacements.  Once cartilage is injured, it is very difficult to repair and its structure, which is critical to its supporting weight, is hard to mimic, according to Fei Wang, director of the Musculoskeletal Tissue Engineering and Regenerative Medicine Program at the National Institute of Arthritis and Musculoskeletal and Skin Diseases in Bethesda, Md. Given the complexity of surgical cartilage-repair, Drs. Mao and Cook’s collaborative landmark study, recently published in The Lancet, in which the entire articular surface of a synovial joint was regenerated provides a viable option for cartilage repair. This kind of biological therapy would be life changing for those nearly 27 million people in the United States that suffer from osteoarthritis and to the significant percentage of those that end up with conventional joint replacement surgery. For Dr. Cook, observing the debilitating effects of osteoarthritis came at an early age watching his grandfather suffer from painful arthritic joints.  Even after the knee replacement surgery, his grandfather eventually was resigned to a wheelchair. Clearly the drive to find a biological alternative to the conventional metal and plastic parts used in joint replacements has been a personal mission for Dr. Cook.  As research on stem cells and their role in regenerative medicine progresses, evident in advancements noted in work including those of Drs. Mao and Cook, we are getting a glimpse of the future of modern medicine as it turns from bionic to patient-specific biological therapy.

Chin J Dent Res. 2010;13(2):95-103.

Liu H, Cao T.

Stem Cell Laboratory, Faculty of Dentistry, National University of Singapore, Singapore.

J Periodontal Implant Sci. 2010 Dec;40(6):265-70. Epub 2010 Dec 31.

Kim HS, Kim KH, Kim SH, Kim YS, Koo KT, Kim TI, Seol YJ, Ku Y, Rhyu IC, Chung CP, Lee YM.

Department of Periodontology and Dental Research Institute, Seoul National University School of Dentistry, Seoul, Korea.

J Craniofac Surg. 2011 Jan;22(1):342-8.

Bulgin D, Hodzic E, Komljenovic-Blitva D.

From the Polyclinic "ME-DENT," Rovinj, Republic of Croatia.

J Cell Mol Med. 2010 Dec 28.

Catón J, Bostanci N, Remboutsika E, De Bari C, Mitsiadis TA.

Clinical and Diagnostic Sciences, Dental Institute, King's College London, London SE1 9RT, United Kingdom Institute of Oral Biology, ZZMK, Faculty of Medicine, University of Zurich, 8032 Zurich, Switzerland Stem Cell Biology Laboratory, Institute of Molecular Biology and Genetics "Alexander Fleming", Vari 16672, Greece Division of Applied Medicine, School of Medicine & Dentistry, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom Departamento de Anatomía y Embriología Humana I, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain.

Cell-based tissue repair of the tooth and -tooth-supporting- periodontal ligament is a new attractive approach that complements traditional restorative or surgical techniques for replacement of injured or pathologically damaged tissues. In such therapeutic approaches, stem cells and/or progenitor cells are manipulated in vitro and administered to patients as living and dynamic biological agents. In this review we discuss the clonogenic potential of human dental and periodontal tissues such as the dental pulp and the periodontal ligament and their potential for tooth and periodontal repair and/or regeneration. We propose novel therapeutic approaches using stem cells or progenitor cells, which are targeted to regenerate the lost dental or periodontal tissue.

J Neurosci Res. 2010 Oct 8.

Xu H, Miki K, Ishibashi S, Inoue J, Sun L, Endo S, Sekiya I, Muneta T, Inazawa J, Dezawa M, Mizusawa H.

Department of Neurology and Neurological Science, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.

De Rosa A, Tirino V, Paino F, Tartaglione A, Mitsiadis T, Feki A, D'Aquino R, Laino L, Colacurci N, Papaccio G.

Seconda Universit&#x00E0; degli Studi di Napoli, Dipartimento di Discipline Odontostomatologiche, Ortodontiche e Chirurgiche, Napoli, Italy; [email protected].

PLoS One. 2010 Sep 14;5(9):e12743.

Egusa H, Okita K, Kayashima H, Yu G, Fukuyasu S, Saeki M, Matsumoto T, Yamanaka S, Yatani H.

Department of Fixed Prosthodontics, Osaka University Graduate School of Dentistry, Suita, Osaka, Japan. [email protected]

Oral Dis. 2010 Jan;16(1):20-8.

Feng F, Akiyama K, Liu Y, Yamaza T, Wang TM, Chen JH, Wang BB, Huang GT, Wang S, Shi S.

Stem Bio Tek Corporation, Taipei, Taiwan.

by Gregory Chotkowski, DMD

A team of researchers at Third Military Medical University in China announced earlier this month that they found transplanted stem cells helpful in the recovery of several spinal cord injuries.

The trial, conducted with rats that had sustained spinal cord damage, found that mesenchymal stem cells – which can differentiate into a variety of different tissues – facilitated repair of damaged nervous system tissue.

This line of research holds promise because the human nervous system – similar in certain ways to that of the trial animals’ – has limited capacity for regeneration, leaving spinal cord injury patients with difficult challenges to overcome. Spine trauma often leads to permanent partial or total paralysis, and sometimes death; 200,000 Americans live with its day-to-day effects.

In a related study, researchers at the University of Adelaide in Australia reported last year in trials involving birds that stem cells obtained from adult teeth, which can be harvested during wisdom tooth extraction and other routine procedures, can induce neuroplasticity within a nervous system.

This is an encouraging step towards devising methods of regrowing and repairing parts of the human nervous system that medicine has previously been unable to heal.

SOURCES

“Functional recovery in acute traumatic spinal cord injury after transplantation of human umbilical cord mesenchymal stem cells”, Hu, Sheng-Li et al

“Adult Human Dental Pulp Stem Cells Differentiate Toward Functionally Active Neurons Under Appropriate Environmental Cues”, Agnes, Arthur et al

“Implanted Adult Human Dental Pulp Stem Cells Induce Endogenous Axon Guidance”, Agniezska, Arthur et al

By Gregory Chotkowski, DMD

Researchers at the Massachusetts Institute of Technology announced this week that they have created a new synthetic substance that will overcome challenges in culturing, or growing, stem cells. What is this  new synthetic substance?

As we have seen time and time again, adult human stem cells hold enormous promise for medicine, offering medicine the possibility to cure a vast number of diseases and grow new organs on demand.

The first challenge – securing a source of personalized stem cells to be used – is being tackled in a variety of ways, including the cryogenic banking of dental stem cells. Dental stem cells are found within commonly-extracted teeth, such as wisdom teeth, and can be preserved indefinitely.

The second challenge – which might more accurately be described as a host of inter-related engineering problems – is the growth and manipulation of stem cells outside of the body. Their enormous power to multiply, divide, and differentiate into virtually any tissue found in the human body is affected by a complex set of environmental, genetic and chemical factors that medical science is attempting to decode and learn to control.

The key to further advances in these decoding efforts is the ability to successfully grow substantial quantities of stem cells in an artificial environment outside of the human body, or tissue engineering. “For therapeutics, you need millions and millions of cells,” says Krishanu Saha, one of the researchers. “If we can make it easier for the cells to divide and grow, that will really help to get the number of cells you need to do all of the disease studies that people are excited about.”

The materials these artificial environments are currently made of – often “a plastic dish coated with a layer of gelatin and then a layer of mouse cells or proteins” – are “notoriously inefficient”, says Saha. A further challenge is that the rodent cells often lead to problems with rejection when the finished products of the stem cell culture are transplanted into human patients.

The MIT researchers, by adjusting various chemical and physical properties, were able to hit upon a configuration that enabled ever-increasing numbers of cells – in the millions – to continue growing and dividing for up to three months.

This is an important step forward towards the easy production of new personalized organs, in a matter of just weeks, outside of the human body – a vision that may become a reality in just decades, if not years.

SOURCES
http://web.mit.edu/newsoffice/2010/stem-cells-0823.html

"Combinatorial development of biomaterials for clonal growth of human pluripotent
stem cells" by Mei, Saha, Bogatyrev, Yang, Hook, Kalcioglu, Cho, Mitalipova, Pyzocha, Rojas, Van Vliet, Davies, Alexander, Langer, Jaenisch, Anderson. Nature Materials, 22 August, 2010.

By Gregory Chotkowski, DMD

Researchers at the University of Barcelona announced that they have successfully treated two patients, 19- and 31-year-old women, who were afflicted with cancer of the trachea. This kind of cancer – the cause of which is unknown – can cause intense pain and interfere with breathing and swallowing.

Doctors used the patients’ own stem cells to grow tracheas, a process which starts with a scaffolding-like tube, for this doctors harvested a trachea from a donor and treated this with detergents to remove all cells that could lead to rejection The trachea now devoid of cellular material was coated with the patient’s own stem cells harvested from bone marrow and the nasal cavity. The newly constructed windpipes were then implanted.

Dr. Paolo Macchiarini, the lead surgeon, explained that two kinds of stem cells were harvested from the patients. Each of these was used to grow tissue to replace the different lining and parts of the windpipe.. Rejection and scarcity of donors – major issues typically associated with transplants – were not an issue here, because the new tissue was newly-grown, and biologically identical to the patients’ own.

While the treatment is in the early clinical developmental stage, the success of the  treatment offers the profound promise of more widespread application in the near future.. This is a very hopeful development because the only treatments currently available for this debilitating type of cancer are chemotherapy and replacement with mechanical devices, both of which have considerable complications and have not been particularly effective.

The patients were released in just several weeks and the operation was deemed a success.  One patient was able to speak just hours after the operations.  Dr. Macchiarini, who participated in a similar trial two years ago, explained that these methods using an individual’s own stem cells could be made to apply to other organs in the future as well: "I'm thinking about the larynx or surgeries involving lungs," he said.

SOURCES
http://abcnews.go.com/Health/Health/
successful-stem-cell-trachea-transplant/story?id=11308383

http://www.macmillan.org.uk/Cancerinformation/Cancertypes/
Tracheawindpipe/Trachealcancer.aspx

http://www.google.com/hostednews/ap/
article/ALeqM5iviB9OISC7d28NW-9m-ONoLHjf3wD9H9F2LO0

By Gregory Chotkowski, DMD

In an encouraging new study for current and future genetic disorder sufferers, led by Children’s Hospital Boston, a new type of potential treatment is emerging, using an ingenious combination of stem cells and gene therapy.

Genetic diseases are caused by abnormalities in an individual’s DNA that can range from a small mutation in a single gene to the addition or subtraction of entire chromosomes, which can occur randomly or be inherited from parents.

One of the most challenging such disorders is SCID, or “bubble boy syndrome” – patients who inherit this disease have a severely compromised immune system, becoming extremely vulnerable to many types of infections and sometimes living in sealed, sterile environments. Most children with the condition perish in their first year: "Providing treatment [to SCID patients] in a timely manner is essential to avoid otherwise fatal infections early in life,” said principal investigator Dr. Luigi Nortarangelo.

It is SCID that is being targeted, in Boston and five other sites around the world, by researchers who hope to demonstrate new, safe, and effective gene therapy treatments. SCID is caused by mutations in certain genes which lead to a very low number of T cells, a core component of the body’s immune system.

Researchers hope to correct the condition by introducing a functioning copy of the defective gene responsible for the disease into  the patients’ own recovered stem cells. These corrected stem cells would then be reintroduced into the patient’s bone marrow – the part of the body where new cells are produced – leading to an increase in the number of T cells and other vital immune system components. Lead U.S. investigator Dr. David Williams noted that the “possibility of curing a disease possibly forever after only one treatment is really amazing.”

Stem cells would play a key role in bringing about this revolutionary new cure, because when receiving the corrected stem cells, it is vital to the patient’s health that the transplanted cells be genetically very close to his or her own. It is this sticking point that makes bone-marrow transplants such a difficult procedure: brothers or sisters who are marrow matches can be donors, but this is rare, and as Children’s Hospital Boston notes, “unrelated matched donor can be prohibitively time-consuming.” Even with a partial match, complications include chemotherapy, life-long dependency on drugs, and graft-versus-host disease.

As this troublesome procedure is currently the only treatment for devastating immune disorders like SCID, there is a significant possibility that this new study and its use of accessible sources of stem cells that can be corrected through this novel approach will provide new hope to patients and their families.

SOURCES

http://clinicaltrials.gov/ct2/show/study/NCT01129544?term=SCID&rank=2

By Gregory Chotkowski, DMD

In an encouraging development for those suffering from lung damage or related disorders, researchers at Yale University have opened the door to a potential breakthrough in respiratory medicine by demonstrating the possibility of regenerating bio-engineered lungs.

These results are particularly hopeful because lung disease – the third-most-common cause of death in the United States, according to the National Institutes of Health – accounts for over 30,000 deaths each month. Human lungs are critical to survival and can only repair themselves at a very low level, falling victim to cancer, infection, and other disorders.

The only treatment currently available is a lung transplant, a costly procedure with 10-year survival rates under 20% and a desperate shortage of available organs. Furthermore, as with many transplants, there is the possibility of rejection, a process wherein an organism’s immune system mistakenly attacks a transplanted organ.

In the Yale study – conducted with rats – the researchers removed much of the tissue from donor lungs, to stave off the possibility of rejection. The result was a natural lung “scaffold”, elegantly saving bioengineers the difficult task of constructing the framework for lungs from scratch – a task made nearly-impossible by their complex shape and innumerable blood vessels.

Next, scientists used newborn lung cells – which, in the case of possible future human trials, may be derived from stem cells – to regrow healthy tissue over the scaffold. This one-week process produced fully-formed lungs, which were mechanically tested and then transplanted into animals.

The results were heartening: the regenerated lungs were implanted successfully and functioned efficiently for a short time. However, long-term success with regenerated lungs depends on the ability to more effectively grow appropriate tissue over the “scaffolding”.

To accomplish this, bioengineers need an appropriate source of a particular type of stem cells – those that they can cause to grow into different kinds of tissue by activating a particular combination of genes.

In a potentially relevant study the same month, a team of researchers at Gifu University in Japan demonstrated a promising, new potential source of the requisite cells. They worked with dental pulp cells – found inside the tooth, and typically discarded after common procedures such as root canals and wisdom tooth extractions.

By activating a specific set of genes in these dental cells, the researchers were able to reprogram them into pluripotent stem cells, or iPS – cells otherwise typically accessible only at or before birth, and valuable for their ability to form nearly any type of human tissue. These stems cells, when derived from teeth, are relatively easy to isolate and handle, making them a potentially indispensable future engine of personal regenerative medicine.

SOURCES

http://www.sciencemag.org/cgi/content/abstract/science.1189345

http://jdr.sagepub.com/content/early/2010/06/11/0022034510366846

By Gregory Chotkowski, DMD

In a breakthrough study published this month in the New England Journal of Medicine, a research team in Italy used stem cell therapy to restore sight to more than three-quarters of blind and vision-impaired patients.

Many of the patients in the study had been blinded by chemical accidents – of which there are nearly 3,000 each year in the United States – or infections, leaving them with damaged corneas. The cornea is the transparent front part of the eye, covering the pupil.

In a healthy eye, the cells of the cornea are constantly dying and being renewed by adult stem cells. In these patients, due to the injuries they sustained, the part of the eye that is home to these stem cells is damaged, and the cornea becomes scarred and cloudy, causing blindness.

The older remedy for this, receiving a cornea transplant, is often problematic because of rejection, wherein the immune system mistakenly attacks the transplanted organ, leading to potentially serious complications.

In this new treatment, doctors took a tiny patch of stem cells from each patient’s healthier eye, cultivated it in a special chemical brew – actually growing new cells – and grafted the resulting tissue into the affected areas of both eyes.

The results of this new form of stem cell therapy were nothing short of incredible: blindness was reversed in 78% of patients, with an additional 13% showing marked improvement. Many had previously undergone multiple unsuccessful operations, and some of the injuries were decades old.

The improvements persisted, even after follow-ups an average of three years after the procedure. Rejection was not an issue, as the patient’s own cells were used. This is the most promising result yet in a series of findings that give hope to those with vision impairments, and is further evidence of the power of stem cells.

Unfortunately, the strength of this kind of therapy– using the patient’s own cells – is also a weakness, because doctors need to harvest a small number of healthy cells to perform the treatment; in cases of severe enough damage to both eyes, the therapy is “not applicable”, according to the research, because there is no source of the patient’s own stem cells to begin with.

There are indications, however, that even this limitation may be overcome in the near future –

by using stem cells from human teeth. Earlier this year, a research team in Brazil showed, in trials conducted with rabbits, that it is not only possible to reconstruct corneas in this way, but surprisingly effective.

J Conserv Dent. 2009 Oct;12(4):131-8.

Nadig RR.

Department of Conservative Dentistry and Endodontics, Dayananda Sagar College of Dental Sciences, Bangalore, Karnataka, India.

J Periodontol. 2010 May 17.

Nampo T, Watahiki J, Enomoto A, Taguchi T, Ono M, Nakano H, Yamamoto G, Irie T, Tachikawa T, Maki K.

Department of Orthodontics, School of Dentistry, Showa University.2-1-1 Kitasenzoku, Ohta-ku, Tokyo 145-8515, Japan.

Glia. 2010 Jul;58(9):1118-32.

Park HW, Lim MJ, Jung H, Lee SP, Paik KS, Chang MS.

Department of Oral Anatomy, Dental Research Institute and School of Dentistry, Seoul National University, 28 Yeongeon-Dong, Jongno-Gu, Seoul 110-749, Republic of Korea.

J Biomech. 2010 May 13.

Kallai I, van Lenthe GH, Ruffoni D, Zilberman Y, Müller R, Pelled G, Gazit D.

Skeletal Biotech Laboratory, The Hebrew University - Hadassah Faculty of Dental Medicine, PO Box 12272, Ein Kerem, Jerusalem 91120, Israel.

Gordana Vunjak-Novakovic a professor of biomedical engineering at Columbia University and a Scientific Advisor to StemSave has solved one of many problems on the way to successful bone implants: how to grow new bones in the anatomical shape of the original.

Dr. Vunjak-Novakovic and her research team have created and nourished two small bones from scratch in their laboratory. The new bones, part of a joint at the back of the jaw, were created with human stem cells. The shape is based on digital images of undamaged bones.

Dr. Vunjak-Novakovic, Dr. Warren L. Grayson and other members of the team used digital images of the joint to guide a machine that carved a three-dimensional replica, called a scaffold, from cleansed bone material. The team turned the bare scaffold into living tissue by putting it into a chamber molded to its exact shape, and adding human cells, typically isolated from bone marrow or liposuctioned fat. A steady source of oxygen, growth hormones, sugar and other nutrients was piped into the chamber, or bioreactor, so the bone would flourish.

“The cells grow rapidly,” Dr. Vunjak-Novakovic said. “They don’t know whether they are in the body or in a culture. They only sense the signals.”

Read entire article

Ishkitiev N, Yaegaki K, Calenic B, Nakahara T, Ishikawa H, Mitiev V, Haapasalo M.

Department of Oral Health, Nippon Dental University, School of Life Dentistry at Tokyo, Tokyo, Japan.

Hwang YJ, Choi JY.

Full Time Lecturer, Department of Oral and Maxillofacial Surgery, Hallym University Dental Hospital, Seoul, South Korea.

Park JB.

From the Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan.

Riekstina U, Cakstina I, Parfejevs V, Hoogduijn M, Jankovskis G, Muiznieks I, Muceniece R, Ancans J.

Faculty of Medicine, University of Latvia, Riga LV-1001, Latvia. [email protected]

d'Aquino R, De Rosa A, Lanza V, Tirino V, Laino L, Graziano A, Desiderio V, Laino G, Papaccio G.

Department of Experimental Medicine, Section of Histology and Embryology, TERM Division, 2nd University of Naples, Naples, Italy.

J Immunol. 2009 Nov 18. [Epub ahead of print]

Zhang Q, Shi S, Liu Y, Uyanne J, Shi Y, Shi S, Le AD.

*Center for Craniofacial Molecular Biology, University of Southern California, School of Dentistry, Los Angeles, CA 90033.

Alge DL, Zhou D, Adams LL, Wyss BK, Shadday MD, Woods EJ, Gabriel Chu TM, Goebel WS.

Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47908, USA.

Arnsdorf EJ, Jones LM, Carter DR, Jacobs CR.

Bone and Joint R&D Center, VA Palo Alto Health Care System, Palo Alto, California, USA. [email protected]

Gomes J, Monteiro BG, Melo GB, Smith RL, Silva MC, Lizier NF, Kerkis A, Cerruti H, Kerkis I.

Ophthalmology, Fed Uni of Sao Paulo, Sao Paulo, Brazil.

Tissue Eng Part B Rev. 2009 Nov 5.

Mao J, Stosich MS, Moioli E, Lee CH, Fu S, Bastian B, Eisig S, Zemnick C, Ascherman J, Wu J, Rohde C, Ahn J.

Columbia University, Biomedical Engineering and Dental Medicine, 630 W. 168 St. - PH 7 East, New York, New York, United States, 10032, 212-305-4475; [email protected].

Private practice, Portland, OR, USA.

BACKGROUND: Predictability has been demonstrated for the long-term success of dental implants placed simultaneously with or after a sinus-augmentation procedure. However, the time required to obtain optimal bone formation can be from 6 to 9 months or longer with grafting materials other than autogenous bone. For this reason, there is interest in a surgical technique that does not require the harvest of autogenous bone but still results in sufficient bone formation within a relatively short time frame. METHODS: The purpose of this case series was to evaluate the bone formation following sinus-augmentation procedures using an allograft cellular bone matrix containing native mesenchymal stem cells. Biopsy and histologic evaluation were performed after approximately 4 months of healing. RESULTS: Histomorphometric analysis revealed an average vital bone content of 33% (range, 22% to 40%) and an average residual graft content of 6% (range, 3% to 7%) for the five cases reported that had an average healing period of 4.1 months (range, 3 to 4.75 months). CONCLUSION: The high percentage of vital bone content, after a relatively short healing phase, may encourage a more rapid initiation of implant placement or restoration when a cellular grafting approach is considered.

Department of Oral and Maxillofacial Surgery, Taleghani Hospital, Dental Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Recently tissue engineering has become available as a regenerative treatment for bone defects; however, little has been reported on the application of tissue engineering for regeneration of cleft defect tissues. Mesenchymal-derived stem cells were applied to different kinds of bone substitute and compared in different animal models, but their usage in human critical defects remained unclear. In this study we report 2 patients with unilateral alveolar cleft, treated with the composite scaffold of demineralized bone mineral and calcium sulphate (Osteoset) loaded with mesenchymal stem cells (MSCs). Computed tomograms showed 34.5% regenerated bone, extending from the cleft walls and bridging the cleft after 4 months in one case and in the other there was 25.6% presentation of bone integrity. The available data revealed the conventional bone substitute was not a suitable scaffold for the MSC-induced bone regeneration.

Genetics Laboratory, Butantan Institute, São Paulo, SP, Brazil.

Abstract Objectives: Limbal stem cells (LSC) are self-renewing, highly proliferative cells in vitro, which express a set of specific markers and in vivo have the capacity to reconstruct the entire corneal epithelium in cases of ocular surface injury. Currently, LSC transplantation is a commonly used procedure in patients with either uni- or bilateral total limbal stem cells deficiency (TLSCD). Although LSC transplantation holds great promise for patients, several problems need to be overcome. In order to find an alternative source of cells that can partially substitute LSC in cornea epithelium reconstruction, we aimed at investigating whether human immature dental pulp stem cells (hIDPSC) would present similar key characteristics as LSC and whether they could be used for corneal surface reconstruction in a rabbit TLSCD model. Materials: We used hIDPSC, which co-express mesenchymal and embryonic stem cell markers and present the capacity to differentiate into derivative cells of the three germinal layers. TLSCD was induced by chemical burn in one eye of rabbits. After 30 days, the opaque tissue formed was removed by superficial keratectomy. Experimental group received undifferentiated hIDPSC, while control group only received amniotic membrane (AM). Both groups were sacrificed after 3 months. Results and conclusions: We have demonstrated, using immunohistochemistry and reverse transcription-polymerase chain reaction, that hIDPSCs express markers in common with LSC, such as ABCG2, integrin beta1, vimentin, p63, connexin 43 and cytokeratins 3/12. They were also capable of reconstructing the eye surface after induction of unilateral TLSCD in rabbits, as shown by morphological and immunohistochemical analysis using human-specific antibodies against limbal and corneal epithelium. Our data suggest that hIDPSCs share similar characteristics with LSC and might be used as a potential alternative source of cells for corneal reconstruction.

Human Genome Research Center, Biosciences Institute, University of São Paulo, n degrees 106, Cidade Universitária São Paulo SP, CEP: 05508-090, Brazil. [email protected]

BACKGROUND: The possibility of using stem cells for regenerative medicine has opened a new field of investigation. The search for sources to obtain multipotent stem cells from discarded tissues or through non-invasive procedures is of great interest. It has been shown that mesenchymal stem cells (MSCs) obtained from umbilical cords, dental pulp and adipose tissue, which are all biological discards, are able to differentiate into muscle, fat, bone and cartilage cell lineages. The aim of this study was to isolate, expand, characterize and assess the differentiation potential of MSCs from human fallopian tubes (hFTs). METHODS: Lineages of hFTs were expanded, had their karyotype analyzed, were characterized by flow cytometry and underwent in vitro adipogenic, chondrogenic, osteogenic, and myogenic differentiation. RESULTS: Here we show for the first time that hFTs, which are discarded after some gynecological procedures, are a rich additional source of MSCs, which we designated as human tube MSCs (htMSCs). CONCLUSION: Human tube MSCs can be easily isolated, expanded in vitro, present a mesenchymal profile and are able to differentiate into muscle, fat, cartilage and bone in vitro.

Most recently, the very first engineered whole organ transplant, using a windpipe made with the patient's own stem cells, was successfully completed by surgeons in Spain. The patient was a 30-year-old woman, whose airways were damaged by tuberculosis and who needed the transplant to save her lung.

The doctors removed a trachea and bronchus from a donor patient who recently died. Using strong chemicals and enzymes, all of the cells were dissolved from the donor trachea, leaving only a fibrous tissue scaffolding made of collagen protein. This structure was used as the framework to repopulate with the woman's own cells. The doctors used two types of the woman's own cells to populate the scaffold — cells lining her own windpipe, and very immature bone marrow cells (adult stem cells), which could be encouraged to form the kind of cells that normally surround the trachea.

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The groundbreaking technology also means for the first time tissue transplants can be carried out without the need for anti-rejection drugs. Five months on the patient, 30-year-old mother-of-two Claudia Castillo, is in perfect health, The Lancet reports. She needed the transplant to save a lung after contracting tuberculosis. The Colombian woman's airways had been damaged by the disease. Scientists from Bristol helped grow the cells for the transplant and the European team believes such tailor-made organs could become the norm. To make the new airway, the doctors took a donor windpipe, or trachea, from a patient who had recently died. Then they used strong chemicals and enzymes to wash away all of the cells from the donor trachea, leaving only a tissue scaffold made of the fibrous protein collagen. This gave them a structure to repopulate with cells from Ms Castillo herself, which could then be used in an operation to repair her damaged left bronchus - a branch of the windpipe.

He said that in 20 years time, virtually any transplant organ could be made in this way.  US scientists have already successfully implanted bladder patches grown in the laboratory from patients' own cells into people with bladder disease. The European research team, which also includes experts from the University of Padua and the Polytechnic of Milan in Italy, is applying for funding to do windpipe and voice box transplants in cancer patients.

Clinical trials could begin five years from now, they said. Between 50,000 and 60,000 people are diagnosed with cancer of the larynx each year in Europe, and scientists say about half them may be suitable candidates for tissue engineering transplants..

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Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital, Harvard School of Dental Medicine, Boston, MA, USA.

PURPOSE: Current strategies for jaw reconstruction require multiple operations to replace bone and teeth. To improve on these methods, we investigated simultaneous mandibular and tooth reconstruction, using a Yucatan minipig model. MATERIALS AND METHODS: Tooth and bone constructs were prepared from third molar tooth tissue and iliac-crest bone marrow-derived osteoblasts isolated from, and implanted back into, the same pig as an autologous reconstruction. Implants were harvested after 12 and 20 weeks and evaluated by x-ray, ultrahigh-resolution volume computed tomographic (VCT), histological, and immunohistochemical analyses. RESULTS: Small tooth structures were identified, and consisted of organized dentin, enamel, pulp, and periodontal ligament tissues, surrounded by new bone. No dental tissues formed in implants without tooth-bud cells, and bone regeneration was observed to a limited extent. Immunohistochemical analyses using tooth-specific and bone-specific antibodies confirmed the identity of regenerated tissues. CONCLUSIONS: This pilot study supports the feasibility of tissue-engineering approaches for coordinated autologous tooth and mandible reconstruction, and provides a basis for future improvement of this technique for eventual clinical use in humans.

Dipartimento di Medicina Sperimentale, Sezione di Istologia ed Embriologia, TESLab, Secondo Ateneo di Napoli, Napoli, Italy.

Dental pulp stem cells (DPSCs) can be found within the "cell rich zone" of dental pulp. Their embryonic origin, from neural crests, explains their multipotency. Up to now, two groups have studied these cells extensively, albeit with different results. One group claims that these cells produce a "dentin-like tissue", whereas the other research group has demonstrated that these cells are capable of producing bone, both in vitro and in vivo. In addition, it has been reported that these cells can be easily cryopreserved and stored for long periods of time and still retain their multipotency and bone-producing capacity. Moreover, recent attention has been focused on tissue engineering and on the properties of these cells: several scaffolds have been used to promote 3-D tissue formation and studies have demonstrated that DPSCs show good adherence and bone tissue formation on microconcavity surface textures. In addition, adult bone tissue with good vascularization has been obtained in grafts. These results enforce the notion that DPSCs can be used successfully for tissue engineering. J. Exp. Zool. (Mol. Dev. Evol.) 310B, 2008. (c) 2008 Wiley-Liss, Inc.

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Department of Cell Biology, University Medical Center Groningen, University of Groningen, The Netherlands.

Hyposalivation induced by exposure of the salivary gland to radiation while treating head and neck cancer patients, can result in xerostomia (dry mouth syndrome), which burdens the patient with oral dryness or pain, dental caries, reduced taste and smell, increased risk for oral infections, hampered speech, and problems with food mastication. Stem cell therapy may be an option to reduce radiation-induced damage to the salivary glands permanently. This Directions in Science article reviews a recent study (Lombaert et al, 2008) using tissue stem cells to regenerate the salivary glands from cells that originate from putative stem cells residing in the ductal compartment. Lombaert et al showed restoration of function of irreversibly damaged mouse submandibular glands after intraglandular injection of an in vitro cultured c-Kit+ cell population containing salivary gland stem cells. The findings raise the prospect of clinical autologous salivary gland stem cell transplantation after radiotherapy.

Department of Tissue Engineering, Nagoya University School of Medicine, Nagoya, Japan. [email protected]

Salivary gland destruction occurs as a result of various pathological conditions such as radiation therapy for head and neck cancer and Sjögren's syndrome. As saliva possesses self-cleaning and antibacterial capability, hyposalivation is known to deteriorate dental caries and periodontal disease. Furthermore, hyposalivation causes mastication and swallowing problems, burning sensation of the mouth and dysgeusia. Currently available treatments for dry mouth are prescription for artificial saliva, moisturizers and medications which induce salivation from the residual tissue. Unfortunately, these treatments cannot restore the acini functions. This review focuses on various efforts to restore the function of damaged salivary gland. First, the possibility of salivary gland regeneration and tissue engineering is discussed with reference to stem cells, growth factors and scaffold materials. Second, the current status of gene transfer to salivary glands is discussed.

The inability to foster angiogenesis – a physiological process involving the growth of new blood vessels from pre-existing vessels – has been a major roadblock in tissue regeneration. Previous approaches have included the use of angiogenic growth factors and the fabrication of artificial blood vessels. However, there are problems associated with these approaches. Among these problems: artificially fabricated blood vessels do not readily branch out and network with host blood vessels, and blood vessels induced by angiogenic growth factors tend to be immature and "leaky."

To overcome these obstacles, a team of Columbia researchers has co-transplanted hematopoietic and mesenchymal stem/progenitor cells to promote the regeneration of vascularized tissues. What they found was that the tissue regenerated in bone more rapidly than when either type of stem cell was used alone.

The work by Jeremy Mao, DDS, Ph.D., published December 15 in PLoS ONE, takes a new approach: rarely have mesenchymal and hematopoietic cells been delivered in combination for the healing of defects and the treatment of diseases – partially due to the separate research communities in which these two cell groups are studied.

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STROKE victims could one day give their back teeth to repair brain injuries, an Adelaide researcher predicts.

A team of scientists is investigating using stem cells harvested from adult teeth to repair brain damage.

It will be led by the newly created Centre for Stem Cell Research, which was launched yesterday at the University of Adelaide.

Almost 100 scientists and 80 students from 18 research groups across Adelaide are involved with the centre, which plans to develop therapies for diseases such as stroke, heart attack, cancer and cystic fibrosis.

It has been established that cells from adult teeth can be used to create stem cells that have the ability to form new brain tissue.

An experiment has begun to see whether these cells can repair stroke damage in the brains of rats.

Dr Simon Koblar of the University of Adelaide said human clinical trials would follow within five years if the experiments worked.

Dr Koblar said most of his patients in the clinic at Queen Elizabeth Hospital "would give gladly some of their teeth" to see even a small improvement in movement and brain function after a stroke.

"At the moment all I can do is, from day to day, say `wait and see'," he said.

Centre director Associate Professor Stan Gronthos was one of the first to realise that teeth stem cells were "a little bit different".

"They have the ability to form different structures in the craniofacial region including brain tissue as well," he said.

Researcher Dr Agnes Arthur helped prove stem cells from adult teeth could make brain cells. Her work has been published in the journal Stem Cells.

She said she wanted to do something that could have clinical implications, "down the track" and was happy with the way the research turned out.

September 15, 2008 11:30pm

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Centro de Investigación Príncipe Felipe, Unit of Cardioregeneration, Valencia, Valencia, Spain; [email protected].

Myocardial infarction is a major public health problem that causes significant mortality despite recent advances in its prevention and treatment. Therefore, approaches based on adult stem cells represent a promising alternative to conventional therapies for this life-threatening condition. Mesenchymal stem cells (MSC) are self-renewing pluripotent cells that have been isolated from multiple tissues and differentiate to various cell types. Here we have analysed the capacity of MSC from human bone marrow (BMSC), adipose tissue (ATSC) and dental pulp (DPSC) to differentiate to cells with a cardiac phenotype. Differentiation of MSC was induced by long-term co-culture with neonatal rat cardiomyocytes (CM). Shortly after the establishment of MSC-CM co-cultures, expression of connexin 43 and the cardiac specific markers Troponin I, &#946;-MHC, Atrial natriuretic peptide (ANP) and &#945;-Sarcomeric actinin was detected in BMSC, ATSC and DPSC. Expression of differentiation markers increased over time in the co-cultures, reaching the highest levels at 4 weeks. Translocation of the transcription factors NKX2.5 and GATA4 to the nucleus was observed in all three cultures of MSC during the differentiation process; moreover, nuclear localization of NKX2.5 and GATA4 correlated with expression of &#945;-Sarcomeric actinin. These changes were accompanied by an increase in myofibril organization in the resulting CM-like cells as analyzed by electron microscopy. Thus, our results provide novel information regarding the differentiation of tissue-specific MSC to cardiomyocytes and support the potential use of MSC in cell-based cardiac therapies.

Center for Research and Education in Technology Evaluation, University of Connecticut School of Dental Medicine, Farmington, Connecticut, USA. [email protected]

To date, the restoration, repair, and replacement of lost and damaged teeth used metals and plastics, nonbiological materials. This type of dentistry has been referred to as "xenodontics." This article discusses the progress in developing a tissue-engineered tooth derived from stem cells. The use of biologically derived replacements for lost and missing teeth is called "biodontics." The technical difficulties that dentists had to overcome historically in restoring, replacing, and repairing lost and damaged teeth are reviewed. The inventiveness and creativity of our professional ancestors in using materials available to restore damaged teeth and to make artificial teeth and denture bases are discussed. This section concludes with the introduction of plastics for both the fabrication of prosthetic teeth and denture bases. The history of root implants is introduced, concluding with the use of titanium. This article concludes by noting that, for the most part, dental schools are just beginning to include implants or computer-aided design (CAD) and computer-aided manufacturing (CAM) into the curriculum and that this process should be accelerated to ensure our graduates are fully prepared to practice efficiently and successfully.

Public release date: 22-Sep-2008

Results of Children's Hospital of Pittsburgh of UPMC study published in journal Cell Stem Cell

In a promising finding for the field of regenerative medicine, stem cell researchers at Children's Hospital of Pittsburgh of UPMC have identified a source of adult stem cells found on the walls of blood vessels with the unlimited potential to differentiate into human tissues such as bone, cartilage and muscle.

The scientists, led by Bruno Péault, PhD, deputy director of the Stem Cell Research Center at Children's Hospital, identified cells known as pericytes that are multipotent, meaning they have broad developmental potential. Pericytes are found on the walls of small blood vessels such as capillaries and microvessels throughout the body and have the potential to be extracted and grown into many types of tissues, according to the study.

"This finding marks the first direct evidence of the source of multipotent adult stem cells known as mesenchymal stem cells. We believe pericytes represent one of the most promising sources of multipotent stem cells that scientists have been searching for in the quest to make regenerative medicine possible," Dr. Péault said. "The encouraging aspect of this source is that blood vessels are the one structure that all tissues in the human body have in common. These cells can be extracted easily and painlessly from convenient sources such as fat tissue, dental pulp, umbilical cord and placental tissue, then grown in culture to large numbers and, possibly, re-injected into the patient to heal a broken bone, a failing joint or an injured muscle."

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Amitabh Avasthi  for National Geographics News  August 27, 2008

Dental pulp from wisdom teeth could be a new source of therapeutic stem cells, Japanese researchers announced recently

Like embryonic stem cells, the new cells—known as mesenchymal stem cells—are capable of developing into a variety of tissues, including bone, cartilage, and fat. These new lines of stem cells can be created without the use of an embryo—possibly sidestepping controversy.

In many countries adults routinely get minor surgeries to remove wisdom teeth.

"The [wisdom] tooth is usually discarded into trash, so there are no ethical concerns," said Hajime Ohgushi, principal research scientist at the National Institute of Advanced Industrial Science and Technology in the Hyogo Prefecture, Japan.

However, unlike embryonic stem cells, the newfound cells cannot morph into almost any type of cell in the body.

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Posted Tue Sep 16, 2008 5:24pm AEST
Updated Tue Sep 16, 2008 6:07pm AEST

University of Adelaide researchers say they are close to repairing stroke-damaged brains using stem cells taken from teeth.

The research is being done at the university's Centre for Stem Cell Research, which has been officially launched at a function in Adelaide.

Project coordinator Dr Simon Koblar says the research involves dental pulp stem cells.

"So we've actually taken them from young people that have impacted molars in their mouth and we remove the tooth and you can break it open and inside the tooth are some stem cells, so you can grow them in a test tube," he explained.

The procedure has been tested on rats and, if all goes to plan, there may be human trials in the next five years.

The research has funding support from the Catholic Church because it avoids the ethical dilemma involved with use of embryonic stem cells.

"The Catholic Church obviously has a moral objection with embryonic stem cells and they decided the best way of doing that would be to offer a grant every two years with groups that use adult stem cell populations," Dr Koblar said.

The new stem cell centre will be used by almost 100 scientists and 80 research students.

Adelaide University hopes it can help put South Australian researchers at the forefront of stem cell research in Australia.

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Could sacrificing a tooth enable some infertile men to father children? That's the goal of researchers in Brazil, who suggest that stem cells from human teeth can be coaxed into becoming sperm by injecting them into the testes of mice.

Irina Kerkis of the Butantan Institute, São Paulo, and her colleagues injected stem cells from the dental pulp of human teeth into the testes of live mice.

The cells seemed to migrate to the tubules where sperm usually mature and differentiate into cells resembling human sperm.

However, the process was inefficient and some of the human cells fused with mouse cells – a problem that would have to be solved before the technique could be used therapeutically.

Baby teeth

The cells were also taken from baby teeth, so it is unclear if the approach would work with teeth from adult men.

"I think we are on the right track, but we need to understand more about the mechanism," says Kerkis, whose team will present the results at the meeting of the European Society of Human Reproduction and Embryology in Barcelona, Spain, on 9 July.

Other researchers are sceptical. It takes human sperm several weeks to develop, yet the Brazilian team's cells seemed to have matured within nine days.

Given that human sperm stem cells have previously failed to mature in mouse testes, it seems unlikely that dental cells would fare better, adds Robin Lovell-Badge of the National Institute for Medical Research in London, UK.

Neuroscience Division, Yerkes National Primate Research Center, Atlanta, USA. [email protected]

BACKGROUND: Chimpanzee dental pulp stem/stromal cells (ChDPSCs) are very similar to human bone marrow derived mesenchymal stem/stromal cells (hBMSCs) as demonstrated by the expression pattern of cell surface markers and their multipotent differentiation capability. RESULTS: ChDPSCs were isolated from an incisor and a canine of a forty-seven year old female chimpanzee. A homogenous population of ChDPSCs was established in early culture at a high proliferation rate and verified by the expression pattern of thirteen cell surface markers. The ChDPSCs are multipotent and were capable of differentiating into osteogenic, adipogenic and chondrogenic lineages under appropriate in vitro culture conditions. ChDPSCs also express stem cell (Sox-2, Nanog, Rex-1, Oct-4) and osteogenic (Osteonectin, osteocalcin, osteopontin) markers, which is comparable to reported results of rhesus monkey BMSCs (rBMSCs), hBMSCs and hDPSCs. Although ChDPSCs vigorously proliferated during the initial phase and gradually decreased in subsequent passages, the telomere length indicated that telomerase activity was not significantly reduced. CONCLUSION: These results demonstrate that ChDPSCs can be efficiently isolated from post-mortem teeth of adult chimpanzees and are multipotent. Due to the almost identical genome composition of humans and chimpanzees, there is an emergent need for defining the new role of chimpanzee modeling in comparative medicine. Teeth are easy to recover at necropsy and easy to preserve prior to the retrieval of dental pulp for stem/stromal cells isolation. Therefore, the establishment of ChDPSCs would preserve and maximize the applications of such a unique and invaluable animal model, and could advance the understanding of cellular functions and differentiation control of adult stem cells in higher primates.

CHU Nantes, pôle Odontologie, 1, place Alexis-Ricordeau, 44042 Nantes, France.

Any clinician dreams to obtain the regeneration of the destroyed organ for his patient. In the human being, the regeneration of complex structures is not possible, except the liver and the bone marrow, which can be regenerated because of the presence of adult stem cells in these tissues. The stem cells have two principal properties: they ensure their self-renewal and they have the ability to differentiate into several cellular types. Using specific markers allowing the identification of the stem cells in bone marrow, stem cells were observed in dental pulp tissues. Although the origin, the identification, and the localization of these stem cells of dental pulp remain under consideration, the optimism in research on stem cells permits to believe that the knowledge on dental stem cells will lead to their use in therapeutics.

d'Aquino R, Papaccio G, Laino G, Graziano A.

Dipartimento di Discipline Odontostomatologiche, Ortodontiche e Chirurgiche, Secondo Ateneo di Napoli (Italy), Naples, Italy.  Stem Cell Rev. 2008 Feb 26

Yagi K, Kojima M, Oyagi S, Ikeda E, Hirose M, Isoda K, Kawase M, Kondoh M, Ohgushi H.  Graduate School of Pharmaceutical Sciences, Osaka University, Suita City, Japan. [email protected]

Fundación Hospital General Universitario, Consorcio Hospital General Universitario de Valencia, Avenida Tres Cruces s/n, 46014 Valencia, Spain.

Human dental pulp contains precursor cells termed dental pulp stem cells (DPSC) that show self-renewal and multilineage differentiation and also secrete multiple proangiogenic and antiapoptotic factors. To examine whether these cells could have therapeutic potential in the repair of myocardial infarction (MI), DPSC were infected with a retrovirus encoding the green fluorescent protein (GFP) and expanded ex vivo. Seven days after induction of myocardial infarction by coronary artery ligation, 1.5 x 10(6) GFP-DPSC were injected intramyocardially in nude rats. At 4 weeks, cell-treated animals showed an improvement in cardiac function, observed by percentage changes in anterior wall thickening left ventricular fractional area change, in parallel with a reduction in infarct size. No histologic evidence was seen of GFP+ endothelial cells, smooth muscle cells, or cardiac muscle cells within the infarct. However, angiogenesis was increased relative to control-treated animals. Taken together, these data suggest that DPSC could provide a novel alternative cell population for cardiac repair, at least in the setting of acute MI.

Departamento de Cirurgia Plástica e Queimaduras, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.

The main aim of this study is to evaluate the capacity of human dental pulp stem cells (hDPSC), isolated from deciduous teeth, to reconstruct large-sized cranial bone defects in nonimmunosuppressed (NIS) rats. To our knowledge, these cells were not used before in similar experiments. We performed two symmetric full-thickness cranial defects (5 x 8 mm) on each parietal region of eight NIS rats. In six of them, the left side was supplied with collagen membrane only and the right side (RS) with collagen membrane and hDPSC. In two rats, the RS had collagen membrane only and nothing was added at the left side (controls). Cells were used after in vitro characterization as mesenchymal cells. Animals were euthanized at 7, 20, 30, 60, and 120 days postoperatively and cranial tissue samples were taken from the defects for histologic analysis. Analysis of the presence of human cells in the new bone was confirmed by molecular analysis. The hDPSC lineage was positive for the four mesenchymal cell markers tested and showed osteogenic, adipogenic, and myogenic in vitro differentiation. We observed bone formation 1 month after surgery in both sides, but a more mature bone was present in the RS. Human DNA was polymerase chain reaction-amplified only at the RS, indicating that this new bone had human cells. The use of hDPSC in NIS rats did not cause any graft rejection. Our findings suggest that hDPSC is an additional cell resource for correcting large cranial defects in rats and constitutes a promising model for reconstruction of human large cranial defects in craniofacial surgery.

Dipartimento di Discipline Odontostomatologiche, Ortodontiche e Chirurgiche, Secondo Ateneo di Napoli, Napoli, Italy.

Stem cells were obtained from deciduous dental pulp of healthy subjects, aged 6-10 years. This stem cell population was cultured, expanded, and specifically selected, detecting using a FACsorter, c-kit, CD34, and STRO-1 antigen expression. Then, c-kit+/CD34+/STRO-1+ cells were replaced in the culture medium added of 20% FBS, leading to osteoblast differentiation. In fact, these cells, after a week, showed a large positivity for CD44, osteocalcin, and RUNX-2 markers. To achieve an adipocytic differentiation, cells, after sorting, were challenged with dexamethason 10(-8) mM in the same culture medium. To obtain myotube fusion, sorted cells were co-cultured in ATCC medium with mouse myogenic C2C12 cells and, after a week, human stem cell nuclei were found to be able to fuse, forming myotubes. Differentiated osteoblasts, as assessed by a large positivity to several specific antibodies, after 30 days of culture and already in vitro, started to secrete an extracellular mineralized matrix, which, 2 weeks later, built a considerable number of 3D woven bone samples, which showed a strong positivity to alkaline phosphatase (ALP), alizarin red, calcein, other than to specific antibodies. These bone samples, after in vivo transplantation into immunosuppressed rats, were remodeled in a lamellar bone containing entrapped osteocytes. Therefore, this study provides strong evidence that human deciduous dental pulp is an approachable "niche" of stromal stem cells, and that it is an ideal source of osteoblasts, as well as of mineralized tissue, ready for bone regeneration, transplantation, and tissue-based clinical therapies. Copyright 2005 Wiley-Liss, Inc.

Institut für Humangenetik, Universität Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany. [email protected]

This review article arranges the current results of stem cell biology for their use in dentistry. There are different types of stem cells, which are applicable for dental treatments. The use of embryonic stem cells, whose possibilities for breeding an artificial tooth were hardly evaluated, is however ethically precarious. On the other side the ethically harmless adult stem cells, which were isolated for example from bone marrow, were little examined for their capability of differentiation into dental tissues. Therefore their forthcoming use in dentistry is rather improbable. However, dental ectomesenchymal stem cells are more promising for dentistry in future. For example dental pulp stem cells (DPSCs) are capable to differentiate into dentin under in vitro conditions. Moreover it is possible to use periodontal ligament (PDL) stem cells and dental follicle precursors for periodontal tissue differentiations in vitro. Recently new populations of stem cells were isolated from the dental pulp and the PDL. These cells distinguish from the initially isolated DPSCs and PDL stem cells in growth and cell differentiation. Therefore stem cell markers are very important for the characterization of dental stem cells. A significant marker for dental stem cells is STRO-1, which is also a marker for bone marrow derived mesenchymal stem cells. Nonetheless dental stem cells are CD45 negative and they express rarely hematopoietic stem cell markers.These research results plead for the participation of dental stem cells in dental practice in future.

Dipartimento di Discipline Odontostomatologiche, Ortodontiche e Chirurgiche, Secondo Ateneo di Napoli, Napoli, Italy.

To harvest bone for autologous grafting is a daily problem encountered by craniofacial and oral surgeons. Stem cells derived from human dental pulp are able to differentiate in osteoblasts and are a potential source of autologous bone produced in vitro. The authors describe their preliminary results in this new field with its potential application in craniomaxillofacial surgery. Dental pulp was gently extracted from 34 human permanent teeth (all third molars) of patients 19 to 37 years of age. After they were digested, the cells were selected using a cytometer for c-kit, STRO-1, CD34, CD45, and then for CD44 and RUNX-2. This study, made on a considerable number of cases, provided evidence that dental pulp is extremely rich in stem cells, which were c-kit+/CD34+/STRO-1+/CD45-, capable of differentiation toward several stromal-derived differentiated cells and mainly osteoblasts. These findings, supported by the large number of cases, are of great interest for tissue regeneration, tissue-based clinical therapies, and transplantation.