Enhancement strategy for effective vascular regeneration following myocardial infarction through a dual stem cell approach

Abstract

Since an impaired coronary blood supply following myocardial infarction (MI) negatively affects heart function, therapeutic neovascularization is considered one of the major therapeutic strategies for cell-based cardiac repair. Here, to more effectively achieve therapeutic neovascularization in ischemic hearts, we developed a dual stem cell approach for effective vascular regeneration by utilizing two distinct types of stem cells, CD31+-endothelial cells derived from human induced pluripotent stem cells (hiPSC-ECs) and engineered human mesenchymal stem cells that continuously secrete stromal derived factor-1α (SDF-eMSCs), to simultaneously promote natal vasculogenesis and angiogenesis, two core mechanisms of neovascularization. To induce more comprehensive vascular regeneration, we intramyocardially injected hiPSC-ECs to produce de novo vessels, possibly via vasculogenesis, and a 3D cardiac patch encapsulating SDF-eMSCs (SDF-eMSC-PA) to enhance angiogenesis through prolonged secretion of paracrine factors, including SDF-1α, was implanted into the epicardium of ischemic hearts. We verified that hiPSC-ECs directly contribute to de novo vessel formation in ischemic hearts, resulting in enhanced cardiac function. In addition, the concomitant implantation of SDF1α-eMSC-PAs substantially improved the survival, retention, and vasculogenic potential of hiPSC-ECs, ultimately achieving more comprehensive neovascularization in the MI hearts. Of note, the newly formed vessels through the dual stem cell approach were significantly larger and more functional than those formed by hiPSC-ECs alone. In conclusion, these results provide compelling evidence that our strategy for effective vascular regeneration can be an effective means to treat ischemic heart disease.

Vascular regeneration and skeletal muscle repair induced by long-term exposure to SDF-1α derived from engineered mesenchymal stem cells after hindlimb ischemia

“…In our previous study, we veri ed that SDF1α-eMSCs were indistinguishable from normal BM-MSCs with respect to their cell morphology and MSC markers (Supplementary Fig. 1a) 21 . However, we con rmed that SDF1α-eMSCs stably secreted human SDF-1α protein, as determined by a human SDF-1α enzymelinked immunosorbent assay (ELISA) assay 21 .…”

“…1a) 21 . However, we con rmed that SDF1α-eMSCs stably secreted human SDF-1α protein, as determined by a human SDF-1α enzymelinked immunosorbent assay (ELISA) assay 21 . Therefore, we expected that the paracrine effects of SDF1α-eMSCs would be stronger than those of BM-MSCs in vitro.…”

Investigation on Electrospun and Solvent-Casted PCL-PLGA Blends Scaffolds Embedded with Induced Pluripotent Stem Cells for Tissue Engineering

“…It is reported in the literature that differentiation of pluripotent stem cells typically results in heterogeneous cellular populations, and even the presence of only a small fraction of osteoblasts can yield positive results in assays of osteoblast gene expression and mineralization [ 61 ]. Eventually, endothelial cells derived from human-induced pluripotent stem cells are reported in the literature with the purpose of large blood vessel regeneration [ 62 ].…”

The hope, hype and obstacles surrounding cell therapy

“…iPSC cultures can provide any number of mature cells. 54 However, given the long iPSC preparation procedures, this may not be adequate when timely intervention is crucial for patients in need of treatment. Therapy after this time may bring some improvement, but it will not be fully effective.…”