Vascular Progenitors From Cord Blood–Derived Induced Pluripotent Stem Cells Possess Augmented Capacity for Regenerating Ischemic Retinal Vasculature

Abstract

Background The generation of vascular progenitors (VP) from human induced pluripotent stem cells (hiPSC) has great potential for treating vascular disorders such as ischemic retinopathies. However, long-term in vivo engraftment of hiPSC-derived VP into retina has not yet been reported. This goal may be limited by the low differentiation yield, greater senescence, and poor proliferation of hiPSC-derived vascular cells. To evaluate the potential of hiPSC for treating ischemic retinopathies, we generated VP from a repertoire of viral-integrated and non-integrated fibroblast and cord blood (CB)-derived hiPSC lines, and tested their capacity for homing and engrafting into murine retina in an ischemia-reperfusion (I/R) model. Methods and Results VP from human embryonic stem cells (hESC) and hiPSC were generated with an optimized hemato-vascular differentiation system. FACS-purification of human embryoid body (hEB) cells differentially expressing endothelial/pericytic markers identified a CD31+ CD146+ VP population with high vascular potency. Episomal CB-iPSC generated these VP with higher efficiencies than fibroblast-iPSC. Moreover, in contrast to fibroblast-iPSC-VP, CB-iPSC-VP maintained expression signatures more comparable to hESC-VP, expressed higher levels of immature vascular markers, demonstrated less culture senescence and sensitivity to DNA damage, and possessed fewer transmitted reprogramming errors. Luciferase transgene-marked VP from hESC, CB-iPSC, and fibroblast-iPSC were injected systemically or directly into the vitreous of retinal I/R-injured adult NOD-SCID mice. Only hESC- and CB-iPSC-derived VP reliably homed and engrafted into injured retinal capillaries, with incorporation into damaged vessels for up to 45 days. Conclusions VP generated from CB-iPSC possessed augmented capacity to home, integrate into, and repair damaged retinal vasculature.

Vascular Wall Progenitor Cells in Health and Disease

“…145 Other work has revealed the phenotypic and functional heterogeneity of iPSC-derived ECs, and has found that iPSCs can be more selectively differentiated into specific EC subtypes (arterial, venous, and lymphatic) by modifying the concentrations of inductive factors in media, such as VEGF-A, VEGF-C, angiopoietin-1, and BMP-4. 146 Transplantation of iPSC-derived ECs and vascular progenitors has augmented tissue regeneration in a variety of preclinical ischemic models, [147][148][149][150] while in reverse, vascular ECs, 151 and blood-derived EPCs 152 have also been used to generate iPSCs with high angiogenic and regenerative capacity.…”

Tankyrase inhibition promotes a stable human naïve pluripotent state with improved functionality

“…For example, although human hematopoietic progenitors are more efficiently reprogrammed than fibroblast donors via standard methods (Eminli et al, 2009;Park et al, 2012;Guo et al, 2014), both donor types generated hiPSCs with diminished and lineage-skewed differentiation potencies that were attributed to the retention of donor epigenetic memory (Kim et al, 2011;Hu et al, 2011). By contrast, hiPSCs reprogrammed efficiently from cord bloodderived CD33 + CD45 (PTPRC) + myeloid progenitors (MPs) (Park et al, 2012) displayed reduced interline variability or differentiation bias (Burridge et al, 2011;Park et al, 2014). These MP-iPSCs generated vascular progenitors (VPs) with less culture senescence, decreased sensitivity to DNA damage, and greater in vivo engraftment potential than VPs generated from standard fibroblast-derived hiPSCs .…”

Patient-specific induced pluripotent stem cells (iPSCs) for the study and treatment of retinal degenerative diseases

“…For instance, Park et al successfully generated cord blood iPSC-derived vascular progenitors and used these cells to repair damaged retinal blood vessels (Park et al, 2014b). However, to our knowledge there is no published data showing the differentiation of iPSC-derived choroidal endothelial cells.…”