Directed and Systematic Differentiation of Cardiovascular Cells From Mouse Induced Pluripotent Stem Cells

Abstract

Background-Induced pluripotent stem (iPS) cells are a novel stem cell population induced from mouse and human adult somatic cells through reprogramming by transduction of defined transcription factors. However, detailed differentiation properties and the directional differentiation system of iPS cells have not been demonstrated. Methods and Results-Previously, we established a novel mouse embryonic stem (ES) cell differentiation system that can reproduce the early differentiation processes of cardiovascular cells. We applied our ES cell system to iPS cells and examined directional differentiation of mouse iPS cells to cardiovascular cells. Flk1 (also designated as vascular endothelial growth factor receptor-2)-expressing mesoderm cells were induced from iPS cells after Ϸ4-day culture for differentiation. Purified Flk1 ϩ cells gave rise to endothelial cells and mural cells by addition of vascular endothelial growth factor and serum. Arterial, venous, and lymphatic endothelial cells were also successfully induced. Self-beating cardiomyocytes could be induced from Flk1 ϩ cells by culture on OP9 stroma cells. Time course and efficiency of the differentiation were comparable to those of mouse ES cells. Occasionally, reexpression of transgene mRNAs, including c-myc, was observed in long-term differentiation cultures. Conclusions-Various

Roles of TGF-β family signaling in stem cell renewal and differentiation

“…Recently, Narazaki et al [56] succeeded in inducing the differentiation of mouse iPS cells into Flk1 + cardiovascular progenitor cells, which generated arterial, venous and lymphatic endothelial cells, and self-beating cardiomyocytes. Utilization of various TGF-β family members will benefit more efficient differentiation of cardiovascular cells from iPS cells established from patients suffering from cardiovascular diseases.…”

Endothelial cells guided by immobilized gradients of vascular endothelial growth factor on porous collagen scaffolds

“…iPS is an emerging technology where a set of transcriptional factors is introduced via a viral vector into somatic cells such as skin fibroblasts to "induce" pluripotency into them. This technology ideally enables the conversion of terminally differentiated cells into embryonic-stem-like cells that can be differentiated into the desired progeny of cells [17,18]. Work is currently underway into exploring the differentiation potential of these cells into myocardial lineage.…”

We heart cultured hearts. A comparative review of methodologies for targeted differentiation and maintenance of cardiomyocytes derived from pluripotent and multipotent stem cells

“…In 2008, three independent research groups reported the derivation of cardiomyocytes from murine iPSC using embryoid body-based and monolayer-based differentiation protocols [19][20][21]. Later, the capacity for derivation of cardiomyocyte-like cells was demonstrated with human iPSC generated using the 4-gene system (OCT4, SOX2, NANOG, and LIN28 transgenes) [15] and the three-gene system (OCT4, SOX2, and KLF4) plus a histone deacetylase inhibitor (valproic acid) [23].…”