Bone-marrow-derived MSCs can promote fracture healing

Fuente: http://www.news-medical.net/news/20150430/Bone-marrow-derived-MSCs-can-promote-fracture-healing.aspx

Mesenchymal stem cells (MSCs) have been transplanted to successfully treat a variety of diseases and conditions. The benefit of using MSCs is their ability to self-renew and differentiate into a variety of specialized cell types, such as osteoblasts (cells contributing to bone formation), chondrocytes (cartilage cells), adipocytes (fat cells), myocardiocytes (the muscle cells that make up the cardiac muscle), and neurons (nervous system cells).

MSCs have shown the ability to modulate the immune response and therefore reduce local inflammation. They can be isolated from a variety of sources, such as adipose (fat) tissues, tendons, peripheral blood, umbilical cord blood and bone marrow. MSCs derived from bone marrow have been among the most successfully transplanted cells, offering therapeutic benefits.

Bone marrow was used as a source for MSCs in three different animal models of disease studies in which MSC transplantation was performed as detailed below and they will be published in future issues of Cell Transplantation.

MSCs promote fracture healing in rats Researchers in Hong Kong, China, who hypothesized that systemic and localized administration of bone-marrow-derived MSCs could promote fracture healing, assigned 48 adult male rats modeled with femoral fractures to four treatment groups. Two groups received MSCs, with one administered systemically and a second locally, four days after the rats were modeled with femoral fractures. The other two rat groups did not receive MSCs.

Five weeks after fracture modeling, it was found that the two groups receiving MSCs, either systemically or locally, had fracture gaps united while fracture gaps were still present in the two groups that did not receive MSCs. Both the locally injected and systemic injected groups demonstrated similar and indistinguishable fracture uniting patterns. However, the presence of generated osteoblasts in the systemically administered group was higher than in the locally injected group. "These findings provide critical insight for developing MSC-based therapies as systemic injection of allogeneic (other donated) MSCs may be a novel treatment method for promoting fracture repair," concluded the researchers.

Scientists move closer to creating cartilage from stem cells

Fuente: http://medicalxpress.com/news/2015-03-scientists-closer-cartilage-stem-cells.html

Scientists have succeeded in producing cartilage formed from embryonic stem cells that could in future be used to treat the painful joint condition osteoarthritis.

In research funded by Arthritis Research UK, Professor Sue Kimber and her team in the Faculty of Life Sciences at The University of Manchester have developed a protocol under strict laboratory conditions to grow and transform embryonic stem cells into cartilage cells (also known as chondrocytes).

Professor Kimber said: "This work represents an important step forward in treating cartilage damage by using embryonic stem cells to form new tissue, although it's still in its early experimental stages."

Their research was published in Stem Cells Translational Medicine.

During the study, the team analysed the ability of embryonic stems cells to become precursor cartilage cells. They were then implanted into cartilage defects in the knee joints of rats.

After four weeks cartilage was partially repaired and following 12 weeks a smooth surface, which appeared similar to normal cartilage, was observed. Further study of this newly regenerated cartilage showed that cartilage cells from embryonic stem cells were still present and active within the tissue.

Developing and testing this protocol in rats is the first step in generating the information needed to run a study in people with arthritis. Before this will be possible more data will need to be collected to check that this protocol is effective and that there are no toxic side-effects.

But researchers say that this study is very promising as not only did this protocol generate new, healthy-looking cartilage but also importantly there were no signs of any side-effects such as growing abnormal or disorganised, joint tissue or tumours. Further work will build on this finding and demonstrate that this could be a safe and effective treatment for people with joint damage.

Chondrocytes created from adult stem cells are currently being experimentally used but as they cannot be currently be produced in large amounts, the procedure is expensive.

With their huge capacity to proliferate, embryonic stem cells, which can be manipulated to form almost any type of mature cell, offer the possibility of high-volume production of cartilage cells. Their use would also be cheaper and applicable to a greater number of arthritis patients, the researchers claim.

"We've shown that the protocol we've developed has strong potential for developing large numbers of chondrogenic cells appropriate for clinical use," added Prof Kimber. "These results thus mark an important step forward in supporting further development toward clinical translation."

Osteoarthritis affects more than eight million people in the UK, and is a major cause of disability. It occurs when cartilage at the ends of bones wears away causing joint pain and stiffness.

Director of research at Arthritis Research UK Dr Stephen Simpson added: "Current treatments of osteoarthritis are restricted to relieving painful symptoms, with no effective therapies to delay or reverse cartilage degeneration. Joint replacements are successful in older patients but not young people, or athletes who've suffered a sports injury.

"Embryonic stem cells offer an alternative source of cartilage cells to adult stem cells, and we're excited about the immense potential of Professor Kimber's work and the impact it could have for people with osteoarthritis."

Journal reference: Stem Cells Translational Medicine

Provided by University of Manchester

Las células madre mesenquimales, aliadas en la regeneración ósea

Fuente: http://traumatologia.diariomedico.com/2015/02/09/area-cientifica/especialidades/traumatologia/celulas-madre-mesenquimales-aliadas-regeneracion-osea

La comunidad científica ha llevado a cabo ensayos clínicos sobre la fiabilidad de la diferenciación de las mesenquimales en osteoblastos como método de reparación ósea localizada.

Paolo Bianco, doctor en Medicina y Cirugía y catedrático de Patología en el departamento de Medicina Experimental de la Universidad de Roma La Sapienza (Italia), se refiere a la reparación de hueso y cartílago a través de la diferenciación de células madre mesenquimales en osteoblastos y condrocitos, respectivamente. "Las células madre mensenquimales vendrían a ser las dobles de las células madre esqueléticas; la única pega es que cuando son trasplantadas muchas se eliminan y de ahí la necesidad de desarrollar técnicas de andamiaje", expuso en el ciclo de conferencias de la Fundación Ramón Areces.

"Se trata de células pluripotentes y adultas con morfología fibroblastoide y plasticidad hacia condrocitos, osteocitos y adipocitos, capaces por tanto de producir varios tipos de células de los tejidos esqueléticos, tales como cartílago, hueso y grasa", precisó Bianco.

Así las cosas, la comunidad científica ha llevado a cabo ensayos clínicos sobre la fiabilidad de la diferenciación de las mesenquimales en osteoblastos como método de reparación ósea localizada. También se espera que las células mesenquimales puedan administrarse a los pacientes para fijar el cartílago de sus articulaciones y evitar farragosas cirugías de reemplazo artificial. "Cómo hacerlo es todavía un punto flaco en este campo de la medicina regenerativa".

Bone stem cells shown to regenerate bones and cartilage in adult mice

Fuente: http://medicalxpress.com/news/2015-01-bone-stem-cells-shown-regenerate.html

The osteochondroretricular stem cell, a newly identified type of bone stem cell that appears to be vital to skeletal development and may provide the basis for novel treatments for osteoarthritis, osteoporosis, and bone fractures. In this illustration of the head of a femur (the thigh bone), osteochondroretricular stem cells are visualized in red. 

A stem cell capable of regenerating both bone and cartilage has been identified in bone marrow of mice. The discovery by researchers at Columbia University Medical Center (CUMC) is reported in the online issue of the journal Cell.

The cells, called osteochondroreticular (OCR) stem cells, were discovered by tracking a protein expressed by the cells. Using this marker, the researchers found that OCR cells self-renew and generate key bone and cartilage cells, including osteoblasts and chondrocytes. Researchers also showed that OCR stem cells, when transplanted to a fracture site, contribute to bone repair.

"We are now trying to figure out whether we can persuade these cells to specifically regenerate after injury. If you make a fracture in the mouse, these cells will come alive again, generate both bone and cartilage in the mouse—and repair the fracture. The question is, could this happen in humans," says Siddhartha Mukherjee, MD, PhD, assistant professor of medicine at CUMC and a senior author of the study.

The researchers believe that OCR stem cells will be found in human bone tissue, as mice and humans have similar bone biology. Further study could provide greater understanding of how to prevent and treat osteoporosis, osteoarthritis, or bone fractures.

"Our findings raise the possibility that drugs or other therapies can be developed to stimulate the production of OCR stem cells and improve the body's ability to repair bone injury—a process that declines significantly in old age," says Timothy C. Wang, MD, the Dorothy L. and Daniel H. Silberberg Professor of Medicine at CUMC, who initiated this research. Previously, Dr. Wang found an analogous stem cell in the intestinal tract and observed that it was also abundant in the bone.

Schematic of the head of a femur (the thigh bone), showing OCR stem cells in red and the growth of bone (green), cartilage and stromal cells. 

"These cells are particularly active during development, but they also increase in number in adulthood after bone injury," says Gerard Karsenty, MD, PhD, the Paul A. Marks Professor of Genetics and Development, chair of the Department of Genetics & Development, and a member of the research team.

The study also showed that the adult OCRs are distinct from mesenchymal stem cells (MSCs), which play a role in bone generation during development and adulthood. Researchers presumed that MSCs were the origin of all bone, cartilage, and fat, but recent studies have shown that these cells do not generate young bone and cartilage. The CUMC study suggests that OCR stem cells actually fill this function and that both OCR stems cells and MSCs contribute to bone maintenance and repair in adults.

The researchers also suspect that OCR cells may play a role in soft tissue cancers.

More information: Gremlin 1 Identifies a Skeletal Stem Cell with Bone, Cartilage, and Reticular Stromal Potential, Volume 160, Issues 1-2, p269–284, 15 January 2015. www.cell.com/cell/abstract/S0092-8674(14)01519-0

Bone stem cells shown to regenerate bone and cartilage in adult mice

Fuente: http://www.eurekalert.org/pub_releases/2015-01/cumc-bsc011515.php

Cells could be exploited to treat osteoarthritis and osteoporosis.

A stem cell capable of regenerating both bone and cartilage has been identified in bone marrow of mice. The discovery by researchers at Columbia University Medical Center (CUMC) is reported in the online issue of the journal Cell. Read more: http://newsroom.cumc.columbia.edu/?p=32074.

The cells, called osteochondroreticular (OCR) stem cells, were discovered by tracking a protein expressed by the cells. Using this marker, the researchers found that OCR cells self-renew and generate key bone and cartilage cells, including osteoblasts and chondrocytes. Researchers also showed that OCR stem cells, when transplanted to a fracture site, contribute to bone repair.

"We are now trying to figure out whether we can persuade these cells to specifically regenerate after injury. If you make a fracture in the mouse, these cells will come alive again, generate both bone and cartilage in the mouse--and repair the fracture. The question is, could this happen in humans," says Siddhartha Mukherjee, MD, PhD, assistant professor of medicine at CUMC and a senior author of the study.

The researchers believe that OCR stem cells will be found in human bone tissue, as mice and humans have similar bone biology. Further study could provide greater understanding of how to prevent and treat osteoporosis, osteoarthritis, or bone fractures.

"Our findings raise the possibility that drugs or other therapies can be developed to stimulate the production of OCR stem cells and improve the body's ability to repair bone injury--a process that declines significantly in old age," says Timothy C. Wang, MD, the Dorothy L. and Daniel H. Silberberg Professor of Medicine at CUMC, who initiated this research. Previously, Dr. Wang found an analogous stem cell in the intestinal tract and observed that it was also abundant in the bone.

"These cells are particularly active during development, but they also increase in number in adulthood after bone injury," says Gerard Karsenty, MD, PhD, the Paul A. Marks Professor of Genetics and Development, chair of the Department of Genetics & Development, and a member of the research team.

The study also showed that the adult OCRs are distinct from mesenchymal stem cells (MSCs), which play a role in bone generation during development and adulthood. Researchers presumed that MSCs were the origin of all bone, cartilage, and fat, but recent studies have shown that these cells do not generate young bone and cartilage. The CUMC study suggests that OCR stem cells actually fill this function and that both OCR stems cells and MSCs contribute to bone maintenance and repair in adults.

The researchers also suspect that OCR cells may play a role in soft tissue cancers.

VIDEO: http://www.eurekalert.org/multimedia/pub/85265.php

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The paper is titled, "Gremlin 1 identifies a skeletal stem cell with bone, cartilage and reticular stromal potential." The other contributors are Daniel L. Worthley (CUMC, University of Adelaide, SA, Australia, South Australian Health and Medical Research Institute, SA, Australia, and Royal Children's Hospital, Vic., Australia), Michael Churchill (CUMC), Jocelyn T. Compton (CUMC), Yagnesh Tailor (CUMC), Meenakshi Rao (CUMC), Yiling Si (CUMC), Daniel Levin (Keck School of Medicine of the University of Southern California, CA), Matthew G. Schwartz (Harvard Medical School, Cambridge, MA), Aysu Uygur (Harvard), Yoku Hayakawa (CUMC), Stefanie Gross (CUMC), Bernhard W. Renz (CUMC), Wanda Setlik (CUMC), Ashley N. Martinez (CUMC), Xiaowei Chen (CUMC), Saqib Nizami (CUMC), Heon Goo Lee (CUMC), H. Paco Kang (CUMC), Jon-Michael Caldwell (CUMC), Samuel Asfaha (CUMC), C. Benedikt Westphalen (CUMC and University Hospital Munich, Ludwig-Maximilians-University Munich - Campus Groβhadern, Munich, Germany), Trevor Graham (Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK), Guangchun Jin (CUMC), Karan Nagar (CUMC), Hongshan Wang (CUMC), Mazen A. Kheirbek (CUMC), Alka Kolhe (CUMC), Jared Carpenter (CUMC), Mark Glaire (CUMC), Abhinav Nair (CUMC), Simon Renders (CUMC), Nicholas Manieri (Washington University in St Louis, MO), Sureshkumar Muthupalani (Massachusetts Institute of Technology, Cambridge, MA), James G. Fox (MIT), Maximilian Reichert (University of Pennsylvania Perelman School of Medicine, Philadelphia, PA), Andrew S. Giraud (CUMC), Robert F. Schwabe (CUMC), Jean-Phillipe Pradere (CUMC and Université Paul Sabatier, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France), Katherine Walton (University of Michigan, Ann Arbor, MI), Ajay Prakash (Michigan), Deborah Gumucio (Michigan), Anil K. Rustgi (Pennsylvania), Thaddeus S. Stappenbeck (Washington), Richard A. Friedman (CUMC), Michael D. Gershon (CUMC), Peter Sims (CUMC), Tracy Grikscheit (Keck School of Medicine of the University of Southern California, Los Angeles, CA), and Francis Y. Lee (CUMC).

The authors declare no financial or other conflicts of interest.

The study was funded by grants from the National Institutes of Health (5U54 CA126513, R01 RHL115145A, AR056246, and EB006834),), the Robert Carroll and Jane Chace Carroll Laboratories, the American Cancer Society, the NH&MRC and Menzies Foundation, Cancer Council SA's Beat Cancer Project on behalf of its donors and the State Government of South Australia through the Department of Health, Gastroenterological Society of Australia, the American Gastroenterological Association, the American Association for Cancer Research, the Royal Australasian College of Physicians, and the Columbia University Ines Mandl Postdoctoral research fellowship.

Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. For more information, visit cumc.columbia.edu or columbiadoctors.org.

The Herbert Irving Comprehensive Cancer Center (HICCC) of Columbia University and New York-Presbyterian Hospital is dedicated to the cure of cancer through innovative basic, clinical, and population-based research and outstanding patient care. HICCC researchers and physicians are dedicated to understanding the biology of cancer and to applying that knowledge to the design of cancer therapies and prevention strategies that reduce its incidence and progression and improve the quality of the lives of those affected by cancer. Initially funded by the National Cancer Institute (NCI) in 1972 and designated comprehensive in 1979, the HICCC is one of 41 NCI-designated comprehensive cancer centers in the United States, of which only three are in New York State. The designation recognizes the Center¹s collaborative environment and expertise in harnessing translational research to bridge scientific discovery to clinical delivery, with the ultimate goal of successfully introducing novel diagnostic, therapeutic, and preventive approaches to cancer. For more information, visit www.hiccc.columbia.edu.

Scientists identify bone cells that could help children who need corrective facial surgery

Fuente: http://medicalxpress.com/news/2014-11-scientists-bone-cells-children-facial.html

Our bones are smart. Bones know that by adolescence it's time to stop growing longer and stronger, and from that point on bones keep their shape by healing injuries.

This question of why bones grow longer and stronger in children, but stay static in adults—yet retain the ability to heal themselves, has long perplexed scientists in the bone regeneration field. But researchers from the University of Michigan, Kyoto University and Harvard University believe they may have unearthed a big piece of this puzzle.

The team discovered that a certain subset of cartilage-making cells, known as chondrocytes, replicate themselves, make other bone cells and drive bone growth—findings that could lead to new treatments for children with facial deformities who normally have to wait until adulthood for corrective surgery.

The study by Dr. Noriaki Ono, U-M assistant professor of dentistry, and colleagues appears online in Nature Cell Biology.

It's long been thought that these chondrocytes die when children reached adolescence and their bones stopped growing, Ono said. However, the fact that bone still heals itself even without chondrocytes caused intense debate among researchers.

Ono's group found that some chondrocytes don't die, but rather transform themselves into other types of bone-growing and bone-healing cells.

"Up until now, the cells that drive this bone growth have not been understood very well. As an orthodontist myself, I have special interest in this aspect, especially for finding a cure for severe bone deformities of the face in children," he said. "If we can find a way to make bones that continue to grow along with the child, maybe we would be able to put these pieces of growing bones back into children and make their faces look much better than they do."

Ono said one of the challenges in the bone and cartilage field is that stem cells haven't really been identified. The only widely accepted idea is that certain stem cells help bones grow and heal, but that's only discussed in the context of adults with bone disorders such as osteoporosis.

Many factors cause craniofacial deformities, and all are devastating to children, he said. In children with Goldenhar syndrome, underdeveloped facial tissues can harm the developing jawbone. Another bone deformity called deformational plagiocephaly causes a child's head to grow asymmetrically.

More information: "A Subset of Chondrogenic Cells Provides Early Mesenchymal Progenitors in Growing Bones" Nature Cell Biology, DOI: 10.1038/ncb3067

Building blocks for cartilage and bones lies in small molecules and stem cells

Fuente: http://www.medicaldaily.com/building-blocks-cartilage-bones-lies-small-molecules-and-stem-cells-306396

Each year, thousands of accident victims, people with arthritis, or children born with congenital defects require bone or cartilage repair. Now scientists have come up with a technique of using small molecules to generate mouse cells that can form bone and cartilage. This technique, developed by scientists at the University of Texas Health Science Center at Houston (UTHealth), Monash University, and RIKEN Centre for Developmental Biology, promises to be less expensive and more feasible than current bone cell generation strategies. The research was recently published in the journal Development.

Current methods of bone and cartilage regeneration use adult stem cells. Stem cells play an important role in replacing or regenerating the diseased tissues. Adult human cells are transformed into cells that function similar to embryonic stem cells. But this method has proven to be very expensive and does not always meet with success.

"Current cell generation strategies generally use proteins to direct the stem cells to give rise to functional cells of interest. Such proteins act on the target cells through multiple mechanisms, not all of which necessarily help to achieve the overall goal [of generating chondrocytes]. In addition, proteins are unstable and expensive to make, and the cost is one of the hurdles that limits the ability of scientists to make the amounts necessary for clinical purposes," said lead researcher Naoki Nakayama in a statement.

To get around this, the team, led by Nakayama, took a different approach and worked on pluripotent stem cells from early mouse embryo. These cells have the potential to transform to any cell type. The team used small molecules to coax the embryonic stem cells to turn into cells called chondrocytes, the only cells that can form cartilage and then bone.

The reason for using small molecules is that they are generally longer-lasting than proteins in culture and also inexpensive to produce on a large scale, says Nakayama. “They can also allow a particular mechanism to be more precisely activated. Such strategies have already been used to replace protein factors with such small molecules to establish a better culture method for maintaining pluripotent embryonic stem cells and for induction of early neural precursor cells from them," he said.

The team also went a step further and used embryonic stem cells and small molecules to generate cells that were morphologically and functionally similar to chondrocyte precursor cells — paraxial mesoderm and sclerotome. These cells give rise to blocks of tissues that aid in the formation of the backbone and disc. When such cartilages was transplanted into mice, they were able to form bone-like structures. 

Because the method can be used to produce large numbers of cartilage-forming chondrocyte precursors, it offers an excellent potential to develop repair mechanisms of damaged bones and cartilage in humans in the future, says the team.

Source: Nakayama N, Zhao Li, Trilok S, et al. Small molecule-directed specification of sclerotome-like chondroprogenitors and induction of a somatic chondrogenesis program from embryonic stem cells. Development. 2014.