Basic Biology V
$1 146 468
Degenerative joint disease, also known as osteoarthritis, currently affects more than 20 million people in the USA alone, making articular cartilage restoration one of the major priorities in medicine. Articular chondrocyte progenitors are likely to be present only early in development, which explains why previous attempts to engineer articular cartilage using adult stem cells have been unsuccessful. Recapitulation of the human chondrogenic program using human pluripotent stem cells (hPSC) may represent a groundbreaking system for cartilage restoration. We hypothesize that regeneration of articular cartilage requires not only generation of structural cartilage cells, but also a supportive “niche” component absent or not fully represented in the adult joint. The overall goal of this research proposal is to dissect the cellular and molecular components of this chondrogenic “niche” essential for the survival, maintenance and expansion of cartilage cells produced from hPSC. The findings from these studies will not only contribute towards our understanding of how articular cartilage is formed during hPSC differentiation, but will also have broad applicability for the production of other types of tissues from hPSC. Most importantly, the ability to control differentiation from hPSC into the articular chondrocyte lineage may provide an unlimited source of matched cells for transplantation in patients with joint cartilage degeneration
Statement of Benefit to California:
The unique combination of pluripotentiality and an unlimited capacity for proliferation have raised the hope that pluripotent stem cells (PSC) will one day provide an inexhaustible source of tissue for transplantation and regeneration. Degenerative joint cartilage disease, also known as osteoarthritis, is one of the most common chronic diseases among Californians, causing significant pain and loss of mobility and impairing earning capacity. Tens of thousands of Californians go through invasive and expensive total joint replacement surgery every year. This proposal explores the question of what unique molecular signals control the survival and maintenance of cartilage cells (also known as chondrocytes) produced during the differentiation of PSC. The research proposed in this application has broad potential benefits for Californians, both through the biological questions it will answer and the relevance of its findings for clinical translation. The development of a human cell culture system that could expand the number of available articular chondrocytes would provide new opportunities for transplantation for patients with cartilage injury or degenerative arthritis and potentially delay or even prevent these patients from needing joint replacement procedures. All the scientific findings and technical tools developed in this proposal will be made available to researchers throughout California, according to the guidelines of the California Institute of Regenerative Medicine
This Fundamental Mechanisms proposal intends to develop a method to produce articular chondrocytes, the cartilage forming cells found in joints, from human pluripotent stem cells (hPSC). Current technologies produce chondrocytes that are predominantly growth plate-like and undergo bone differentiation, rather than the articular cartilage forming cells required to treat osteoarthritis and related diseases. The applicant proposes to test the hypothesis that cells present in a novel niche close to articular cartilage produce a microenvironment that is required for the formation, maintenance and survival of articular chondrocytes. Three specific aims are proposed, including in vitro co-culture and in vivo testing. Significance and Innovation - The inability to produce articular chondrocytes has stagnated the field. If the proposed experiments succeed and produce functional articular chondrocytes, this would be a big step towards solving a major stumbling block to developing a stem cell-based therapy for osteoarthritis. - The idea that a "niche" environment is needed is not particularly new, but the proposal that the particular cell type identified in the applicant’s preliminary studies is required for articular chondrocyte formation from embryonic stem cells (ESCs) is interesting, innovative and highly significant. - While there was some debate regarding whether all the studies proposed were truly mechanistic, reviewers were enthusiastic about the potential impact of all the proposed studies. Feasibility and Experimental Design - The entire experimental design was well-presented and the specific aims were well-justified. The experimental design utilizes sound technology. Overall, the feasibility of the project is very high and the strengths in the experimental design outweigh the minor weaknesses. - Experiments to test the hypothesis that niche cells can inhibit hypertrophy and increase articular chondrocyte appear to be straightforward and are supported by strong preliminary data. However, the PI did not discuss expected outcomes and alternative approaches were not offered. - The aim to test the role of a relevant signaling pathway in regulating articular cartilage formation from stem cells was considered feasible. However, it is somewhat preliminary, since it is dependent of the results from the previous aim.. - Reviewers considered the in vivo studies to be somewhat risky; however, this work will provide a direct test of the proposal’s core hypothesis. - Necessary equipment and core facilities appear to be available to the PI and team of researchers. Principal Investigator (PI) and Research Team - Though somewhat junior, the PI has relevant publications that appear in reputed scientific journals. The PI appears to be highly qualified to lead the project. - The team assembled has extensive experience in the field that is required to perform the proposed studies. The overall team of investigators is strong and collaborating investigators have committed sufficient time and salary support. - Strong letters of institutional support are included with the proposal. Responsiveness to the RFA - The proposal is responsive to the RFA; it targets a key cellular mechanism, and human PSC derived cells are critical to the research.