Optimizing stem cells for cardiac repair: Current status and new frontiers in regenerative cardiology

Abstract

Cell therapy has the potential to improve healing of ischemic heart, repopulate injured myocardium and restore cardiac function. The tremendous hope and potential of stem cell therapy is well understood, yet recent trials involving cell therapy for cardiovascular diseases have yielded mixed results with inconsistent data thereby readdressing controversies and unresolved questions regarding stem cell efficacy for ischemic cardiac disease treatment. These controversies are believed to arise by the lack of uniformity of the clinical trial methodologies, uncertainty regarding the underlying reparative mechanisms of stem cells, questions concerning the most appropriate cell population to use, the proper delivery method and timing in relation to the moment of infarction, as well as the poor stem cell survival and engraftment especially in a diseased microenvironment which is collectively acknowledged as a major hindrance to any form of cell therapy. Indeed, the microenvironment of the failing heart exhibits pathological hypoxic, oxidative and inflammatory stressors impairing the survival of transplanted cells. Therefore, in order to observe any significant therapeutic benefit there is a need to increase resilience of stem cells to death in the transplant microenvironment while preserving or better yet improving their reparative functionality. Although stem cell differentiation into cardiomyocytes has been observed in some instance, the prevailing reparative benefits are afforded through paracrine mechanisms that promote angiogenesis, cell survival, transdifferentiate host cells and modulate immune responses. Therefore, to maximize their reparative functionality, ex vivo manipulation of stem cells through physical, genetic and pharmacological means have shown promise to enable cells to thrive in the post-ischemic transplant microenvironment. In the present work, we will overview the current status of stem cell therapy for ischemic heart disease, discuss the most recurring cell populations employed, the mechanisms by which stem cells deliver a therapeutic benefit and strategies that have been used to optimize and increase survival and functionality of stem cells including ex vivo preconditioning with drugs and a novel “pharmaco-optimizer” as well as genetic modifications.

Decline in cellular function of aged mouse c‐kit+ cardiac progenitor cells

“…; Der Sarkissian et al . ). We show here that β‐catenin, SDF‐1 and TGF‐β gene expression can be upregulated in young CPCs in response to Dex treatment whereas these responses are completely absent in aged cells.…”

3D bioprinting for cardiovascular regeneration and pharmacology

“…An alternative interventional approach involves stem cell therapy, such as cell injection into the myocardium. This approach is surgically less invasive, but has been shown to have low viability and weak host cell integration [51,58–60]. Therefore, there is an urgent need to address these challenges to effective CVD treatment through the development of new therapeutic strategies.…”

“…Some factors were identified early as important components for inducing maturation of CMs from different sources such as: supplementation of an oxygen carrier, perfluorocarbon (PFC), media supplementation with L-thyroxine or, replacement of serum, triiodothyronine (T3) and hydrocortisone, as well as B-27 Supplement, cytokines, retinoic acid, and growth factors (such as Activin A, bone morphogenetic protein 4 (BMP4), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), and others) [9,12,58,147,150]. As such, cardiomyocytes can be generated by reprogramming cells.…”

Stem Cell Therapy in Heart Diseases – Cell Types, Mechanisms and Improvement Strategies

“…Pharmacological pre-conditioning represents a convenient and cost effective technique to stimulate the regenerative activity of SCs. As these cells exert their therapeutic effects on damaged tissue mainly by paracrine signaling, drug pre-treatment was applied to promote their secretion activity [394]. For example, incubation with oxytocin increased the release of cytokines in rat MSCs, including bFGF, CXCR4 and EGF [395].…”

“…Numerous studies have proven that preconditioning at low oxygen levels can stimulate intrinsic cell defense mechanisms, leading to improved cell survival and positive effects on SC efficiency [394,418,419]. For example, CDC sheets subjected to hypoxic conditions markedly increase angiogenesis by 25% in the infarction border zone and significantly reduce collagen deposition in mice [420].…”