Therapeutic Effects of Mesenchymal Stromal Cells Require Mitochondrial Transfer and Quality Control

Abstract

Due to their beneficial effects in an array of diseases, Mesenchymal Stromal Cells (MSCs) have been the focus of intense preclinical research and clinical implementation for decades. MSCs have multilineage differentiation capacity, support hematopoiesis, secrete pro-regenerative factors and exert immunoregulatory functions promoting homeostasis and the resolution of injury/inflammation. The main effects of MSCs include modulation of immune cells (macrophages, neutrophils, and lymphocytes), secretion of antimicrobial peptides, and transfer of mitochondria (Mt) to injured cells. These actions can be enhanced by priming (i.e., licensing) MSCs prior to exposure to deleterious microenvironments. Preclinical evidence suggests that MSCs can exert therapeutic effects in a variety of pathological states, including cardiac, respiratory, hepatic, renal, and neurological diseases. One of the key emerging beneficial actions of MSCs is the improvement of mitochondrial functions in the injured tissues by enhancing mitochondrial quality control (MQC). Recent advances in the understanding of cellular MQC, including mitochondrial biogenesis, mitophagy, fission, and fusion, helped uncover how MSCs enhance these processes. Specifically, MSCs have been suggested to regulate peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α)-dependent biogenesis, Parkin-dependent mitophagy, and Mitofusins (Mfn1/2) or Dynamin Related Protein-1 (Drp1)-mediated fission/fusion. In addition, previous studies also verified mitochondrial transfer from MSCs through tunneling nanotubes and via microvesicular transport. Combined, these effects improve mitochondrial functions, thereby contributing to the resolution of injury and inflammation. Thus, uncovering how MSCs affect MQC opens new therapeutic avenues for organ injury, and the transplantation of MSC-derived mitochondria to injured tissues might represent an attractive new therapeutic approach.

Astragalus polysaccharides augment BMSC homing via SDF-1/CXCR4 modulation: a novel approach to counteract peritoneal mesenchymal transformation and fibrosis

“…The therapeutic success of MSCs is closely tied to their efficiency of transplantation. In 2023, MSCs were reported to ameliorate injury by facilitating mitochondrial transfer, which necessitates an optimal contact range [30]. Consequently, optimizing transplantation strategies and The methodology of MSC intervention in PF is currently subject to debate.…”

Mitochondria in the Central Nervous System in Health and Disease: The Puzzle of the Therapeutic Potential of Mitochondrial Transplantation

“…These astrocyte-derived mitochondria rescued the nearby neurons in mice subjected to focal cerebral ischemia [ 139 ]. Mitochondrial transfer between cells has been studied as a potential therapeutic tool, mostly using mesenchymal stromal cells (MSCs) as donors of healthy mitochondria, in various disease models including respiratory, cardiac, and neurological diseases [ 68 , 136 , 140 , 141 , 142 , 143 , 144 ].…”

Bridging the gap between in vitro and in vivo models: a way forward to clinical translation of mitochondrial transplantation in acute disease states

“…The direct transplantation of autologous mitochondria, however, ensures treatment can be delivered both effectively and rapidly to the target organ. Although it is important to note that there are several endogenous pathways to restore mitochondrial function and health following injury by intercellular transfer of mitochondria from mesenchymal stromal cells (MSC) [15,16]. Mitochondrial transfer has also been suggested as a central mediator of the therapeutic efficacy of MSC-based therapies, as reviewed in Mukkala et al [16].…”