Potent immunomodulation and angiogenic effects of mesenchymal stem cells versus cardiomyocytes derived from pluripotent stem cells for treatment of heart failure

Abstract

Background Optimal cell type as cell-based therapies for heart failure (HF) remains unclear. We sought to compare the safety and efficacy of direct intramyocardial transplantation of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and human induced pluripotent stem cell-derived mesenchymal stem cells (hiPSC-MSCs) in a porcine model of HF. Methods Eight weeks after induction of HF with myocardial infarction (MI) and rapid pacing, animals with impaired left ventricular ejection fraction (LVEF) were randomly assigned to receive direct intramyocardial injection of saline (MI group), 2 × 10 8 hESC-CMs (hESC-CM group), or 2 × 10 8 hiPSC-MSCs (hiPSC-MSC group). The hearts were harvested for immunohistochemical evaluation after serial echocardiography and hemodynamic evaluation and ventricular tachyarrhythmia (VT) induction by in vivo programmed electrical stimulation. Results At 8 weeks post-transplantation, LVEF, left ventricular maximal positive pressure derivative, and end systolic pressure-volume relationship were significantly higher in the hiPSC-MSC group but not in the hESC-CM group compared with the MI group. The incidence of early spontaneous ventricular tachyarrhythmia (VT) episodes was higher in the hESC-CM group but the incidence of inducible VT was similar among the different groups. Histological examination showed no tumor formation but hiPSC-MSCs exhibited a stronger survival capacity by activating regulatory T cells and reducing the inflammatory cells. In vitro study showed that hiPSC-MSCs were insensitive to pro-inflammatory interferon-gamma-induced human leukocyte antigen class II expression compared with hESC-CMs. Moreover, hiPSC-MSCs also significantly enhanced angiogenesis compared with other groups via increasing expression of distinct angiogenic factors. Conclusions Our results demonstrate that transplantation of hiPSC-MSCs is safe and does not increase proarrhythmia or tumor formation and superior to hESC-CMs for the improvement of cardiac function in HF. This is due to their immunomodulation that improves in vivo survival and enhanced angiogenesis via paracrine effects. Electronic supplementary material The online version of this article (10.1186/s13287-019-1183-3) contains supplementary material, which is available to authorized users.

Immunomodulation by systemic administration of human-induced pluripotent stem cell-derived mesenchymal stromal cells to enhance the therapeutic efficacy of cell-based therapy for treatment of myocardial infarction

“…This offers an unlimited “ off-the-shelf ” cell source with predictable therapeutic efficacy 12 , 13 . We have demonstrated that hiPSC-MSCs have better proliferative capacity, survival and therapeutic efficacy for myocardial repair than BM-MSCs 12 or embryonic stem cell-derived CMs 14 . Compared with BM-MSCs, hiPSC-MSCs are more immune-privileged due to their insensitivity to pro-inflammatory interferon -γ- induced human leukocyte antigen (HLA) class II expression 15 .…”

Mechanism and therapeutic effect of umbilical cord mesenchymal stem cells in inflammatory bowel disease

“…Liao et al . 37 reported that transplantation of human induced pluripotent stem cell-derived mesenchymal stem cells (hiPSC-MSCs) is safe for the improvement of cardiac function in heart failure (HF). They found this is due to their immunomodulation that improves in vivo survival and enhanced angiogenesis via paracrine effects.…”

miR‐155‐5p inhibition rejuvenates aged mesenchymal stem cells and enhances cardioprotection following infarction

“…Cardiac function in each mouse was assessed by transthoracic echocardiography (Ultramark 9; Soma Technology) at baseline (before MI), 1, or 28 days following MI. LVEF and LVFS were calculated as previously described (Liao et al, 2019).…”

“…Over the last few decades, mesenchymal stem cell (MSC)‐based therapy has emerged as a novel alternative treatment for MI (Kim et al, 2018; Teerlink et al, 2017). Accumulating evidence has demonstrated that transplantation of MSCs can attenuate cardiac remodeling and improve heart function recovery following MI by inhibiting cardiomyocyte apoptosis, increasing angiogenesis, and rejuvenating cardiac muscle cells (Liao et al, 2019; Zhang et al, 2017, 2019). However, the functions of MSCs dramatically decline with aging, as evidenced by increased cellular senescence, impaired proliferative capacity, and decreased paracrine effects, thereby heavily limiting their cardioprotective effects following MI (Liu et al, 2014; Zhang et al, 2018).…”