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RN1-00534-1: Interactions Between Stem Cells and Cartilage in Health and Disease
Recommendation: Not recommended for funding
Public Abstract (provided by applicant)
Arthritis is the result of degeneration of cartilage (the tissue lining the joints) and leads to pain and limitation of function. Arthritis and other rheumatic diseases are among the most common of all health conditions and are the number one cause of disability in the United States. The annual economic impact of arthritis in the U.S. is estimated at over $65 billion, representing more than 2% of the gross domestic product. The prevalence of arthritic conditions is also expected to increase as the population increases and ages in the coming decades. Current treatment options for osteoarthritis include pain relief and joint replacement surgery.
Stem cells have tremendous potential for treating disease and replacing or regenerating the diseased tissue. This grant proposal will be valuable in weighing options for using stems cells in arthritis. It is very important to know the effect of aging on stems cells and how stem cell replacement might effectively treat the causes of osteoarthritis .
In Aim 1 we will find out if stem cells can improve the function of the cells in diseased cartilage. In Aim 2 we will find out if injured cartilage can harm and kill stem cells. In Aim 3 we will find out if arthritic cartilage can signal stem cells to migrate into the diseased tissue and start repairing the tissue. In Aim 4 we will test whether stem cells can improve the healing of cartilage after surgery.
Stem cells fight disease and repair tissues in the body. If this is true we anticipate that stem cells implanted in arthritic cartilage may also treat the arthritis in addition to producing tissue to heal the defect in the cartilage. An approach that heals cartilage defects as well as treats the underlying arthritis would be very valuable. If our research is successful this could lead to new ways to treat cartilage with or without stem cells. Treating cartilage degeneration would have a positive impact on the large numbers of patients who suffer from arthritis as well as in reducing the economic burden created by arthritis.
Statement of Benefit to California (provided by applicant)
California has been at the forefront of biomedical research for more than 40 years and is internationally recognized as the biotechnology capital of the world. The recent debate over the moral and ethical issues of stem cell research have slowed the progress of scientific discoveries in this field especially in the US. The CIRM is a unique institute that fosters ethical stem cell research in California. The CIRM also serves as an exemplary model for similar programs in other states and countries.
This grant proposal falls under the mission statement of the CIRM of funding innovative and untested research. The proposal will generate preliminary yet novel results in the treatment of cartilage degeneration and osteoarthritis and explore the potential use of tissue engineered products from stem cells. At a minimum new insights in the role of stem cell as anti-arthritic agents will be gained. If successful, this will further validate the significance of the CIRM program and help maintain California’s leading position at the cutting edge of biomedical research.
Review
SYNOPSIS: The proposal explores the use of human stem cells for repair of articular cartilage in the treatment of osteoarthritis. The PI proposes to investigate whether human embryonic stem cells (hESC) or mesenchymal stem cells (MSC) have an anti-arthritic effect on human chondrocytes in vitro and whether they have roles for enhancing matrix synthesis and assembly, promoting cartilage healing, function and density. Effects of disease state and age will also be assessed.
STRENGTHS AND WEAKNESSES OF THE RESEARCH PLAN: The strengths of this proposal are the expertise of the applicant and his/her collaborators for ESC and for chondrocyte research, and the great need for repairing cartilage due to disease or trauma. Also, the utilization of multiple in vitro models of disease is innovative and significant.
Four different and complementary hypotheses are postulated to explore the roles of hESC and hMSC in cartilage healing and osteoarthritis. Each hypothesis is tested in a set of studies that constitute one specific aim. There is no unifying hypothesis, and it is not explained how the obtained data will be integrated, interpreted and utilized. Thus, the proposal appears disjoint with four rather independent and open-ended aims. Also, the proposal suffers from lack of detail on research design and methods.
In each set of studies, the PI plans to use a panel of cells, comprising hESC, various MSC, and human articular chondrocytes. It is unclear how these cells are going to be derived. In particular, derivation of hMSC from hESC is still an unresolved problem. For other cells, standard protocols exist, but these need to be specified. Sources of the healthy and osteoarthritic cartilage that will be used are also not specified, beyond the statement that the former will come from tissue banks and the latter from patients. Although preliminary studies establish the rationale for some of the proposed studies, there is concern whether some experiments will give clear answers. For instance, it will be difficult to distinguish the effect from the added stem cells and the potentially endogenous stem cells that the collaborator has reported exist in human articular cartilage.
QUALIFICATIONS AND POTENTIAL OF THE PRINCIPAL INVESTIGATOR: The investigator received a medical degree 25 years ago, and became a Research Fellow at the applicant institution in 1994. S/he has directed research there since 2001, and was appointed to Assistant Professor in 2005. S/he received a PhD in Bioengineering from a leading university in 2007. S/he has published a number of papers in specialty journals, and several of these previous studies won awards. S/he has completed a NIH grant and has another pending NIH award.
The PI’s career development plan is less well developed than others but s/he has a unique combination of expertise in chondrocyte biology and bioengineering. The career development plan builds on his/her previous work and is focused on activities that will result in the status of an independent investigator. The proposed collaborations are a promising sign of expanding his/her expertise into stem cells.
INSTITUTIONAL COMMITMENT TO PRINCIPAL INVESTIGATOR: The PI is considered an integral part of a section at the applicant institution. S/he has directed the basic science research there since 2001 but has only recently, in 2005, been appointed as Assistant Professor (tenure-track). One reviewer felt that based on the PI’s statement that the full faculty appointment was dependent on securing independent funding, it is not clear that there is strong commitment for the PI’s independence by the institution. The institution has a good track record in supporting their faculty.
DISCUSSION: Although the reviewers agreed that the applicant is a qualified orthopedist with expertise in chondrocyte biology, and that s/he is targeting an important problem in medicine, i.e. cartilage repair, they expressed concern about his/her proposal in several areas. The research plan lacks detail, is disjointed, and does not provide a clear rationale for the proposed co-culture experiments or a description as to how the collected information will be integrated. This left the reviewers uncertain whether the proposed experiments will yield useful information. It is also unclear whether the PI will be able to procure the fresh human tissues s/he proposes to utilize in some of the studies.
Although s/he only recently earned a PhD and was appointed Assistant Professor, the applicant earned his/her medical degree 25 years ago, and has been Director of Research for many years, thus s/he has apparently reached a more advanced career stage than intended for funding under this RFA. Furthermore, the career development plan is not well worked out, no clear mentoring strategies or review criteria are presented, and the level of institutional commitment was considered marginal.
The following Working Group members had a conflict of interest with this application and were therefore recused from participating in review of, discussion of, and voting on the application:
- None