Funding opportunities

Induced Pluripotent Stem Cells for Tissue Regeneration

Funding Type: 
Basic Biology III
Grant Number: 
RB3-05232
Principle Investigator: 
Funds requested: 
$1 341 064
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
Induced pluripotent stem cells (iPSCs) have tremendous potential for patient-specific cell therapies, which bypasses immune rejection issues and ethical concerns for embryonic stem cells (ESCs). However, to fully harness the therapeutic potential of iPSCs, many fundamental issues of cell transplantation remain to be addressed, e.g., how iPSC-derived cells participate in tissue regeneration, which type of cells should be derived for specific therapy, and what kind of matrix is more effective for cell therapies. The goal of this project is to use iPSC-derived neural crest stem cells (NCSCs) and nerve regeneration as a model to address these fundamental issues of stem cell therapies. NCSCs are multipotent and can differentiate into cell types in all three germ layers (including neural, vascular, osteogenic and chondrogenic cells), which makes NCSC a valuable model to study stem cell differentiation and tissue regeneration. Peripheral nerve injuries and demyelinating diseases (e.g., multiple sclerosis, familial dysautonomia) affect millions of people. Stem cell therapy is a promising approach to cure these diseases, which will have broad impact on healthcare. This project will advance our understanding of how extracellular microenvironment (native or engineered) regulates stem cell fate and behavior during tissue regeneration, and whether stem cells such as iPSC-NCSCs and differentiated cells such as iPSC-Schwann cells have different therapeutic effects. The results from this project will provide insights that will facilitate the translation of stem cell technologies into therapies for nerve injuries, demyelinating diseases and many other disorders that may be treated with iPSC-NCSCs.
Statement of Benefit to California: 
Induced pluripotent stem cells (iPSCs), especially iPSCs without the integration of reprogramming factors into the genome, are valuable to model disease and to generate autologous cells for therapies. Understanding the role and differentiation of iPSC-derived cells in tissue regeneration will facilitate the translation of stem cell technologies into clinical applications. iPSC-derived neural crest stem cells (NCSCs) can differentiate into a variety of cell types, and hold promise for the therapies of diseases such as nerve injuries, demyelinating diseases, spina bifida, vascular diseases, osteoporosis and arthritis. The isolation and characterization of iPSC-NCSCs will provide a basis for their broad applications in tissue regeneration and disease modeling. This project will use peripheral nerve regeneration as a model to address the fundamental issues of using iPSC-NCSCs for therapies. Peripheral nerve injuries (over 800,000 cases in the United States every year) are very common following traumatic injuries and major surgeries (e.g., removing tumor), which often require surgical repair. Stem cell therapies can accelerate nerve regeneration and avoid the degeneration of muscle and other tissues lack of innervation. Since iPSC-NCSCs can promote the myelination of axons, the therapies for nerve injuries could also be adopted to treat demyelinating diseases. In many cases of stem cell therapies, matrix and scaffold materials are needed to enhance cell survival and achieve local delivery. The studies on appropriate matrix for stem cell delivery will provide a rational basis for designing and optimizing materials for stem cell therapies. The fundamental issues addressed in this project, such as the differentiation and signaling of transplanted cells, the therapeutic effects of cells at the different stages of differentiation and the roles of delivery matrix/materials, will have implications for stem cell therapies in many other tissues. Overall, the results from this project will advance our knowledge on stem cell differentiation and function during tissue regeneration, help us translate the knowledge into clinical applications, and benefit the health care in California and our society.
Review Summary: 
Project Synopsis: This project is focused on mechanisms of peripheral nerve regeneration and the contributions of neural crest stem cells (NCSCs) and Schwann cells derived from human induced pluripotent stem cells (hiPSCs) to support this process. The proposed research will employ a specific delivery material seeded with support cells for nerve regeneration. Potential for nerve regeneration will be evaluated in an immunodeficient rat model with analysis of electrophysiological, anatomical, and behavioral recovery. The first specific aim is to investigate the role of paracrine signaling on NCSC-mediated regeneration. The second aim is to compare the effects of hiPSC-derived NCSCs with hiPSC-derived Schwann cells on regeneration. The third specific aim is to examine the effects of substrate stiffness on both differentiation of Schwann cells in vitro and on nerve regeneration in vivo. Significance and Innovation: - The project is focused on the significant problem of peripheral nerve regeneration. - Study results could substantially advance the development of methods for supporting axonal regeneration. - Use of NCSCs and the delivery material represents a novel and innovative approach. Feasibility and Experimental Design: - The project is supported by appropriate and promising preliminary data. - The PI has convincingly demonstrated the major methodologies and the ability to produce the delivery material and hiPSC-derived NCSCs. - Reviewers expressed some concern about reproducibility and robustness of NCSC derivation procedures. - Appropriate assays needed to evaluate the quality and the extent of regeneration are well established. - Reviewers were concerned that the applicant had not adequately considered or addressed problems of cell survival on the delivery material in vivo. Principal Investigator (PI) and Research Team: - The PI has appropriate expertise and experience in bioengineering and stem cell biology and is well qualified to conduct the proposed research. - The co-investigator is a highly accomplished neurobiologist with expertise in neural development and regeneration. - The quality of the PI and research team are a significant strength of the proposal. Responsiveness to the RFA: - Reviewers judged the proposal as responsive to the RFA in that it addresses some basic molecular and cellular mechanistic elements of NCSCs and the influence of the stem cell microenvironment. - Some project aspects were viewed as peripheral to the RFA focus but worthwhile in that they address the translational potential of hiPSCs.
Conflicts: 

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