iPSC‐derived human mesenchymal stem cells improve myocardial strain of infarcted myocardium

Abstract

We investigated global and regional effects of myocardial transplantation of human induced pluripotent stem cell (iPSC)-derived mesenchymal stem cells (iMSCs) in infarcted myocardium. Acute myocardial infarction (MI) was induced by ligation of left coronary artery of severe combined immunodeficient mice before 2 × 105 iMSCs or cell-free saline were injected into peri-infarcted anterior free wall. Sham-operated animals received no injection. Global and regional myocardial function was assessed serially at 1-week and 8-week by segmental strain analysis by using two dimensional (2D) speckle tracking echocardiography. Early myocardial remodelling was observed at 1-week and persisted to 8-week with global contractility of ejection fraction and fractional area change in saline- (32.96 ± 14.23%; 21.50 ± 10.07%) and iMSC-injected (32.95 ± 10.31%; 21.00 ± 7.11%) groups significantly depressed as compared to sham control (51.17 ± 11.69%, P < 0.05; 34.86 ± 9.82%, P < 0.05). However, myocardial dilatation was observed in saline-injected animals (4.40 ± 0.62 mm, P < 0.05), but not iMSCs (4.29 ± 0.57 mm), when compared to sham control (3.74 ± 0.32 mm). Furthermore, strain analysis showed significant improved basal anterior wall strain (28.86 ± 8.16%, P < 0.05) in the iMSC group, but not saline-injected (15.81 ± 13.92%), when compared to sham control (22.18 ± 4.13%). This was corroborated by multi-segments deterioration of radial strain only in saline-injected (21.50 ± 5.31%, P < 0.05), but not iMSC (25.67 ± 12.53%), when compared to sham control (34.88 ± 5.77%). Improvements of the myocardial strain coincided with the presence of interconnecting telocytes in interstitial space of the infarcted anterior segment of the heart. Our results show that localized injection of iMSCs alleviates ventricular remodelling, sustains global and regional myocardial strain by paracrine-driven effect on neoangiogenesis and myocardial deformation/compliance via parenchymal and interstitial cell interactions in the infarcted myocardium.

Towards the standardization of stem cell therapy studies for ischemic heart diseases: Bridging the gap between animal models and the clinical setting

“…The advantages and limitations of each stem cell with regard to the possible emergence of ethical concerns (symbolized by ¥), the invasiveness and collection (from + to ++++), the isolation procedure, the abundance (from + to ++++), expansion and proliferation rate, the transdifferentiation capacity, the paracrine effects or/and cardiomyogenic potential, the survival and engraftment capacity as well as the immunogenic, oncogenic or teratogenic risks is given in the accessory side tables. The left table abridges bone marrow-derived stem cells [3,[19][20][21]27,28], cortical bone-derived stem cells [32,33], adipose tissue-derived stem cells [34,37,39,41] and gestation-related stem cells [42][43][44][45][46][47][48][49]51,54] and the right table abridges cardiac stem cells [57,59,60], skeletal muscle stem cells [62,63,66] and induced pluripotent stem cells [67,[69][70][71]. The human body scheme was constructed with images sourced from Servier Medical Art (http://www.servier.com/ Powerpoint-image-bank) and Cientic website (http://www.cientic.com/).…”

“…1), though these cells are readily available, as their progenitors are somatic cells, bypassing the ethical concerns related to the collection of ESC [67][68][69][70]. Again, paracrine activity is believed to be the main mechanism of iPSC action through, for instance, angiogenesis stimulation [71].…”

“…the absence of signs of myocardial structural and functional recovery [15,34,44,45,62,71,75] or the manifestation of adverse outcomes, such as arrhythmia [36]. These can be surpassed mainly by one of three alternatives, namely by electing a different stem cell type, by refining a population of stem cells or by adjusting the cell dosage/number of administrations (Box 3, Fig.…”

Microfluidic Single-Cell Analysis of Transplanted Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes After Acute Myocardial Infarction

“…Different cell types, including mesenchymal stem cells (MSCs), cardiac progenitor cells (CPCs), cardiosphere-derived cells (CDCs), embryonic stem cells (ESCs), and induced pluripotent stem cells (iPSCs), have been investigated in both pre-clinical and clinical studies 5-11 , but overall the studies yielded variable results and the basic mechanisms that underlie efficacious cell therapy remain unclear 12 . It has been proposed that the transplanted cells are able to release angiogenic factors, protect cardiomyocytes from apoptotic cell death, and recruit resident cardiac stem cells that facilitate cardiac repair 13 .…”

A comprehensive guide to telocytes and their great potential in cardiovascular system

“…Despite the fact that this method seems to be unrelated to TCs, it was observed that 4 weeks after transplantation endogenous and exogenous cardiac TCs appeared and intermingled in the infarction zone. What is the most important is the fact that recovery of their network in ischaemic area coincided with increased angiogenesis and improvement of myocardial strain (43,44).…”