Stem Cell Metabolism: Powering Cell-Based Therapeutics

Abstract

Cell-based therapeutics for cardiac repair have been extensively used during the last decade. Preclinical studies have demonstrated the effectiveness of adoptively transferred stem cells for enhancement of cardiac function. Nevertheless, several cell-based clinical trials have provided largely underwhelming outcomes. A major limitation is the lack of survival in the harsh cardiac milieu as only less than 1% donated cells survive. Recent efforts have focused on enhancing cell-based therapeutics and understanding the biology of stem cells and their response to environmental changes. Stem cell metabolism has recently emerged as a critical determinant of cellular processes and is uniquely adapted to support proliferation, stemness, and commitment. Metabolic signaling pathways are remarkably sensitive to different environmental signals with a profound effect on cell survival after adoptive transfer. Stem cells mainly generate energy through glycolysis while maintaining low oxidative phosphorylation (OxPhos), providing metabolites for biosynthesis of macromolecules. During commitment, there is a shift in cellular metabolism, which alters cell function. Reprogramming stem cell metabolism may represent an attractive strategy to enhance stem cell therapy for cardiac repair. This review summarizes the current literature on how metabolism drives stem cell function and how this knowledge can be applied to improve cell-based therapeutics for cardiac repair.

LIN28a induced metabolic and redox regulation promotes cardiac cell survival in the heart after ischemic injury

“…LIN28a promotes energetic activity by increasing both oxidative phosphorylation and glycolysis in adult CTSCs. Metabolism has been shown recently as a critical determinant of stem cell fate and function [ 26 ]. Since LIN28a is a master regulator of cellular metabolism [ 25 ], whether reintroduction of LIN28a in adult CTSCs alters metabolism was assessed.…”

Label-free imaging to track reprogramming of human somatic cells

“…S2a-j ). On average, the fraction of protein-bound FAD (FAD α 1 ) first decreases from its levels in EPCs to those in IMs and then increases during the IM to iPSC level, which could be reflective of the OXPHOS burst 27– 29 ( Fig. S2h ).…”

“…However, pluripotent stem cells favor glycolysis, in a manner reminiscent of the Warburg effect in cancer cells 23,24 . During reprogramming, somatic cells thus undergo a metabolic shift from OXPHOS to glycolysis 25,26 , triggered by a transient OXPHOS burst, resulting in initiation and progression of reprogramming to iPSCs [27][28][29] . Recent evidence also indicates that this metabolic shift occurs prior to changes in gene expression and that the modulation of glycolytic metabolism or OXPHOS alters reprogramming efficiency 24,30,31 .…”

Energy Metabolism in Osteogenic Differentiation and Reprogramming: A Possible Future Strategy for Periodontal Regeneration

“…The transition from MSCs to mature osteoblasts employs dynamic metabolic preferences. Moreover, the specific environment of each MSC may be diversified by substrate and oxygen availability, leading to different metabolic states (33)(34)(35)(36)(37). Understanding energy metabolism in stem cells may guide in involvement of metabolic reprogramming during osteoblast differentiation.…”