The study of stem cells will revolutionize the practice of medicine in coming years. At the NYU Hospital for Joint Diseases Musculoskeletal Center of Excellence, in studies led by Drs. Glyn Palmer and Mukundan Attur, we have embarked on a collaborative project to study the use of stem cells to regenerate and repair cartilage in osteoarthritis (OA).
Many approaches have met with some success in programming chondrocytes to regenerate cartilage tissue in vitro for subsequent transplantation into diseased joints. However, it has been difficult to generate sufficient numbers of cartilage-producing chondrocytes capable of synthesizing stable, functional articular cartilage. Obtaining chondrocytes from donor tissue is also problematic. Chondrocytes are in very limited supply in the body, and their harvest would require an additional surgical procedure prior to transplantation. The use of mesenchymal stem cells (MSCs) can potentially overcome these limitations.
|Mesenchmyal stem cells induced to differentiate in vitroMesenchmyal stem cells (MSCs, top), aspirated from a variety of tissues, can be induced to differentiate into cartilage in vitro. Stimulated with various biological agents, MSCs can form fat cells (adipocytes, B); bonebuilding cells (osteoblasts, C); or cartilage producing (chondrocytes, D). This cartilage matrix could be used for transplantation in an arthritic joint.
|MSCs can be isolated from multiple tissue sources—including bone marrow, fat and skin—and obtained through minimally invasive procedures such as needle aspiration or liposuction. As stem cells, MSCs have the capacity to regenerate themselves, enabling in vitro expansion to large numbers for cell replacement therapy. When stimulated with specific biological agents, these cells can be induced to form several types of tissues including chondrocytes that could be transplanted into an arthritic joint. Utilizing MSCs obtained from the discarded tissues of patients undergoing hip replacement surgery makes regeneration of cartilage in OA patients a feasible goal.
In an effort to improve the efficiency of cartilage generation from MSCs, we have recently begun to investigate the role of micro RNAs (miRNAs) in chondrocyte differentiation. These non-coding RNA molecules act by targeting multiple genes to regulate fundamental cellular pathways controlling cell identity and fate. Using gene expression profiling, we have examined miRNA signatures following stimulation of MSCs to cartilage and bone. In each case we have identified several candidate miRNAs that are specifically associated with chondrocyte (cartilage) and osteoblast (bone) formation (see Figure above). Work is underway to determine if these miRNAs can improve cartilage and bone formation and whether they can be exploited to uncover novel pathways that control cell fate determination in MSCs. These studies should aid tissue regeneration strategies by enabling controlled differentiation of stem cells into the desired cell type, so that the transplanted cells can form a functional and durable repair tissue.
The project was funded by a challenge gift from the William and Linda Steere Foundation to Dr. Steven Abramson. Mr. Steere is an NYU Trustee and former CEO and Chairman of Pfizer. We are also making use of findings from a gene discovery project done in collaboration with Daiichi-Sankyo Pharmaceuticals of Japan. During this project, we have discovered approximately 20 genes that are abnormally expressed in OA cartilage, 5 of which have been chosen as high value targets for regeneration. We will use these target genes in experiments using gene transfection techniques to determine whether MSCs can be delivered to and restore diseased articular cartilage. Our goal is one day to reduce disability and improve function and quality of life for millions of patients with OA.