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Improving Stem Cell Therapy for Diabetes by Naïve Reversion of iPSCs

Review of “Vascular progenitors generated from tankyrase inhibitor-regulated naïve diabetic human iPSC potentiate efficient revascularization of ischemic retina” from Nature Communications by Stuart P. Atkinson

A previous study from the laboratory of Elias T. Zambidis (Johns Hopkins School of Medicine, Baltimore, MD, USA) [1] established that the transplantation of vascular progenitor cells derived from human induced pluripotent stem cells (hiPSCs) may represent a promising therapeutic strategy to reverse the ischemic death of retinal pericytes and endothelial cells observed in diabetic patients [2]. However, the highly variable differentiation efficiency and reduced in vivo functionality of iPSC-derived vascular progenitor cells have limited their therapeutic application. 

Now, the Zambidis team return in a new study [3] that evaluates the induction of the naïve pluripotent state in hiPSCs through exposure to an optimized chemical cocktail that includes XAV939, a small molecule tankyrase/PARP (poly ADP ribose polymerase) inhibitor [4], as a means to remove lineage-specific priming and enhance vasculogenic differentiation potential. Overall, Park et al. believe that this strategy has the potential to improve both the differentiation and overall therapeutic potential of hiPSCs derived from both healthy and diseased donors.

Reporting in Nature Communications, the authors stably reverted conventionally reprogrammed and cultured (“primed”) hiPSCs derived from type-1 diabetic donor fibroblasts to a naïve epiblast-like state via the exposure of cells to a small molecule cocktail composed of LIF, the GSK3β inhibitor CHIR99021, the MEK inhibitor PD0325901, and the small molecule tankyrase/PARP inhibitor XAV939 [4]. Following differentiation into vascular progenitor cells, in vitro analysis established cells derived from naïve hiPSCs expanded more efficiently, possessed greater genomic integrity, and displayed higher in vitro vascular functionality than cells derived from primed hiPSCs. Furthermore, in vivo analysis in a murine model of ischemic retinopathy also revealed that naïve iPSC-derived vascular progenitor cells displayed enhanced survival, migration, and engraftment into the neural retinal layer vasculature when compared to vascular progenitor cells derived from primed hiPSCs.

To discover how the conversion of primed hiPSCs to the naïve state enhanced the function of vascular progenitor cells, the authors undertook an in-depth epigenetic analysis. Fascinatingly, their analysis of DNA methylation and histone modification patterns established that naïve hiPSCs tightly regulated lineage-specific gene expression and displayed a de-repressed epiblast-like epigenetic state that was poised for multi-lineage transcriptional activation. Therefore, the authors hypothesize that reversion of primed hiPSCs to a naive state with the tankyrase/PARP inhibitor-containing small molecule cocktail may permit the more effective “resetting” of the cellular epigenetic state, thereby erasing epigenetic donor cell memory or disease-associated epigenetic aberrations and endowing hiPSCs with an elevated level of epigenetic plasticity, an expanded differentiation potential, and an improved functionality that would combine to enhance the therapeutic potential of iPSC-derived cells.

For more on how the conversion of primed hiPSCs into the naïve pluripotent state may aid the treatment of diabetes-related vascular problems (and more!), stay tuned to the Stem Cells Portal!

References

  1. Park Tea S, Bhutto I, Zimmerlin L, et al., Vascular Progenitors From Cord Blood–Derived Induced Pluripotent Stem Cells Possess Augmented Capacity for Regenerating Ischemic Retinal Vasculature. Circulation 2014;129:359-372.
  2. Zheng L, Gong B, Hatala DA, et al., Retinal Ischemia and Reperfusion Causes Capillary Degeneration: Similarities to Diabetes. Investigative Ophthalmology & Visual Science 2007;48:361-367.
  3. Park TS, Zimmerlin L, Evans-Moses R, et al., Vascular progenitors generated from tankyrase inhibitor-regulated naïve diabetic human iPSC potentiate efficient revascularization of ischemic retina. Nature Communications 2020;11:1195.
  4. Zimmerlin L, Park TS, Huo JS, et al., Tankyrase inhibition promotes a stable human naïve pluripotent state with improved functionality. Development 2016;143:4368.