Understanding and leveraging cell metabolism to enhance mesenchymal stem cell transplantation survival in tissue engineering and regenerative medicine applications

Abstract

In tissue engineering and regenerative medicine, stem cell-specifically, mesenchymal stromal/stem cells (MSCs)-therapies have fallen short of their initial promise and hype. The observed marginal, to no benefit, success in several applications has been attributed primarily to poor cell survival and engraftment at transplantation sites. MSCs have a metabolism that is flexible enough to enable them to fulfill their various cellular functions and remarkably sensitive to different cellular and environmental cues. At the transplantation sites, MSCs experience hostile environments devoid or, at the very least, severely depleted of oxygen and nutrients. The impact of this particular setting on MSC metabolism ultimately affects their survival and function. In order to develop the next generation of cell-delivery materials and methods, scientists must have a better understanding of the metabolic switches MSCs experience upon transplantation. By designing treatment strategies with cell metabolism in mind, scientists may improve survival and the overall therapeutic potential of MSCs. Here, we provide a comprehensive review of plausible metabolic switches in response to implantation and of the various strategies currently used to leverage MSC metabolism to improve stem cell-based therapeutics.

Substantial Overview on Mesenchymal Stem Cell Biological and Physical Properties as an Opportunity in Translational Medicine

“…In Vitro experiments have confirmed these results, as crossroads of main survival signaling pathways, like ERK1/2, BDNF, CREB or MAP kinases, are targeted and activated [86,88]. Nevertheless, the angiogenic effect is not granted by the sole soluble mediators, rather depending on oxygen level and crosstalk with an often hostile tissue microenvironment, limiting the metabolism of MSC and determining their poor viability after transplantation [89], which still represents an unresolved limitation to the success of many MSC-based clinical trials.…”

FOXO3-engineered human mesenchymal progenitor cells efficiently promote cardiac repair after myocardial infarction

“…A major challenge of MPC-based therapy resides in the massive loss of transplanted cells upon delivery, which is a yet-to-be-resolved issue that significantly compromises the therapeutic benefits. The poor retention may be attributed to various intrinsic and extrinsic factors such as pro-apoptotic stressors, inflammation, hypoxia, and oxidative stress (Salazar-Noratto et al, 2020). Genetic activation of FOXO3 has been demonstrated to increase the resistance of MPCs to oxidative stress-induced apoptosis (Yan et al, 2019).…”

Hypoxic Preconditioning as a Strategy to Maintain the Regenerative Potential of Mesenchymal Stem Cells

“…Hypoxic preconditioning results in increased glycolytic metabolism and decreased tricarboxylic acid (TCA) cycle and oxidative phosphorylation. This mechanism leads to decreased mitochondrial ROS production and increase in the levels of antioxidant enzymes [52,56]. Unbalanced redox homeostasis can cause stem cells aging and decreased proliferation.…”