Mesenchymal Stem Cells and Their Conditioned Medium Improve Integration of Purified Induced Pluripotent Stem Cell–Derived Cardiomyocyte Clusters into Myocardial Tissue

Abstract

Induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) might become therapeutically relevant to regenerate myocardial damage. Purified iPS-CMs exhibit poor functional integration into myocardial tissue. The aim of this study was to investigate whether murine mesenchymal stem cells (MSCs) or their conditioned medium (MScond) improves the integration of murine iPS-CMs into myocardial tissue. Vital or nonvital embryonic murine ventricular tissue slices were cocultured with purified clusters of iPS-CMs in combination with murine embryonic fibroblasts (MEFs), MSCs, or MScond. Morphological integration was assessed by visual scoring and functional integration by isometric force and field potential measurements. We observed a moderate morphological integration of iPS-CM clusters into vital, but a poor integration into nonvital, slices. MEFs and MSCs but not MScond improved morphological integration of CMs into nonvital slices and enabled purified iPS-CMs to confer force. Coculture of vital slices with iPS-CMs and MEFs or MSCs resulted in an improved electrical integration. A comparable improvement of electrical coupling was achieved with the cell-free MScond, indicating that soluble factors secreted by MSCs were involved in electrical coupling. We conclude that cells such as MSCs support the engraftment and adhesion of CMs, and confer force to noncontractile tissue. Furthermore, soluble factors secreted by MSCs mediate electrical coupling of purified iPS-CM clusters to myocardial tissue. These data suggest that MSCs may increase the functional engraftment and therapeutic efficacy of transplanted iPS-CMs into infarcted myocardium.

Regionally diverse mitochondrial calcium signaling regulates spontaneous pacing in developing cardiomyocytes

“…(miPSC-CM) were prepared by methods described previously [34, 35] and were used in experiments probing the pacemaker current, I f (Fig. 7).…”

Pro-elastogenic effects of bone marrow mesenchymal stem cell-derived smooth muscle cells on cultured aneurysmal smooth muscle cells

“…adipose tissue), to be sufficient to evoke in vivo wound healing/tissue repair and regeneration in different tissue types (Cantinieaux et al ., ; Song et al ., ). Conditioned culture medium (CCM) containing these paracrine factors (cytokines, growth factors), generated in in vitro MSC cultures in real time, or collected and then concentrated, have also been demonstrated to improve cellular health in cultures of diseased cells in vitro (Rubach et al ., ; Fitzpatrick et al ., ) and restore tissue/organ state and function in vivo (Cantinieaux et al ., ; Song et al ., ). On the basis of these earlier findings, in this first study, we investigated whether and how real‐time exposure of EaRASMCs to trophic factors generated by co‐cultured BM‐MSC‐derived SMLCs impacts their matrix synthesis potential.…”

The diverse roles of hydrogel mechanics in injectable stem cell transplantation

“…In therapies that rely on paracrine secretion for therapeutic efficacy, multiple cell doses over time may be necessary to maintain a sufficient level of cell-secreted therapeutic factors, thereby complicating clinical translation [26-29]. In therapies that require transplanted cell integration into the host tissue, poor differentiation into specialized cell types may limit new tissue formation and function [30] and can lead to the formation of teratomas [24,31,32]. Overcoming these challenges may require the use of structural biomaterial supports that provide instructive mechanical cues to the transplanted cells.…”