Safeguarding the genome is essential for cells’ proper functions, and more importantly for safe and efficacious applications involving pluripotent stem cells and adult stem cells. However, how pluripotent or somatic stem cells maintain genome integrity during self-renewal, differentiation, and reprogramming is still largely unknown. We recently identified a small molecule drug that exhibits unprecedented abilities in maintaining and enhancing genome stability of pluripotent stem cells under stress conditions. The proposed studies aim to uncover the small molecule’s mechanisms and utilities in human pluripotent and adult stem cells. These studies will lead to improved understanding to safeguard stem cell genome, provide a safer and more robust approach in stem cell ex vivo expansion, and allow new therapeutic development toward treating diseases and aging associated with genome instability as well as promoting in vivo stem cell protection.
The proposed studies will lead to improved understanding to safeguard stem cell genome, provide a safer and more robust approach in stem cell ex vivo expansion, and allow new therapeutic development toward treating diseases and aging associated with genome instability as well as promoting in vivo stem cell protection.
This fundamental mechanism application addresses the issue of genomic instability that occurs during stem cell reprogramming and replication, an issue that is important to stem cell-based therapies in humans. The overall objective of the study is to define the mechanistic basis of a small molecule, identified by the PI, to preserve genomic integrity of pluripotent stem cells during replication, differentiation, and outgrowth. The PI plans to identify specific pathways induced by the small molecule and proposes several approaches to identify molecular targets of the small molecule. Finally, the utility of the small molecule in preserving genome integrity in cells with a propensity for genome instability will be assessed.
Significance and Innovation
- The reviewers raised some concerns over the relevance of genomic instability in pluripotent stem cells, as this appears to be a somewhat controversial area in the field.
- The proposal is not innovative.
- The proposal makes use of a small molecule identified by the PI, and found the claims that it demonstrates “unprecedented” effects on preserving genomic integrity to be overstated.
- Because genomic instability may be a feature of pluripotent stem cell manipulation, the PI’s findings are potentially relevant for most, if not all, stem cell-related therapies.
Moreover, the protective effects of the small molecule on genome integrity may prove useful beyond stem cell applications.
Feasibility and Experimental Design
- The proposed studies are sound and some have been supported by preliminary data, though reviewers differed in their opinions regarding the quality of preliminary data.
-Some of the analysis proposed for Aim 2 may not be entirely appropriate for this mechanistic track.
- Given the PI’s track record, the reviewers were optimistic regarding the feasibility of the proposed studies. However a major concern raised was the lack of evidence that the same results would be relevant for human cells.
Principal Investigator (PI) and Research Team
- The PI is well established in the field and has identified markers and regulators of embryonic stem cell potency and has defined algorithms for stem cell differentiation.
-The complete team has not been identified and specific bioinformatics support beyond core facilities was not specified. However, institutional facilities were considered excellent.
Responsiveness to the RFA
- Proposal fits the criteria for the fundamental track.
- Ali Brivanlou
- Chad Cowan