Mitochondrial Transfer and Regulators of Mesenchymal Stromal Cell Function and Therapeutic Efficacy

Abstract

Mesenchymal stromal cell (MSC) metabolism plays a crucial role in the surrounding microenvironment in both normal physiology and pathological conditions. While MSCs predominantly utilize glycolysis in their native hypoxic niche within the bone marrow, new evidence reveals the importance of upregulation in mitochondrial activity in MSC function and differentiation. Mitochondria and mitochondrial regulators such as sirtuins play key roles in MSC homeostasis and differentiation into mature lineages of the bone and hematopoietic niche, including osteoblasts and adipocytes. The metabolic state of MSCs represents a fine balance between the intrinsic needs of the cellular state and constraints imposed by extrinsic conditions. In the context of injury and inflammation, MSCs respond to reactive oxygen species (ROS) and damage-associated molecular patterns (DAMPs), such as damaged mitochondria and mitochondrial products, by donation of their mitochondria to injured cells. Through intercellular mitochondria trafficking, modulation of ROS, and modification of nutrient utilization, endogenous MSCs and MSC therapies are believed to exert protective effects by regulation of cellular metabolism in injured tissues. Similarly, these same mechanisms can be hijacked in malignancy whereby transfer of mitochondria and/or mitochondrial DNA (mtDNA) to cancer cells increases mitochondrial content and enhances oxidative phosphorylation (OXPHOS) to favor proliferation and invasion. The role of MSCs in tumor initiation, growth, and resistance to treatment is debated, but their ability to modify cancer cell metabolism and the metabolic environment suggests that MSCs are centrally poised to alter malignancy. In this review, we describe emerging evidence for adaptations in MSC bioenergetics that orchestrate developmental fate decisions and contribute to cancer progression. We discuss evidence and potential strategies for therapeutic targeting of MSC mitochondria in regenerative medicine and tissue repair. Lastly, we highlight recent progress in understanding the contribution of MSCs to metabolic reprogramming of malignancies and how these alterations can promote immunosuppression and chemoresistance. Better understanding the role of metabolic reprogramming by MSCs in tissue repair and cancer progression promises to broaden treatment options in regenerative medicine and clinical oncology.

Metabolomics in Bone Research

“…Metabolomics is one of the key methodologies to study these processes and deepen the understanding of osteogenesis and osteoclastogenesis and their relationship with bone diseases. MSCs, the precursor of osteoblasts, predominantly utilize glycolysis as the energy source within the bone marrow; however, the energy metabolism shifts to oxidative phosphorylation during the differentiation [9,10]. Hypoxia-inducible factor 1 α (HIF-1α) works as a regulator of MSC energy metabolism during osteogenic and chondrogenic differentiation [11].…”

“…MSCs have been shown to grow and proliferate in the glycolysis pathway in hypoxic condition. At the same time, they undergo a metabolic shift to the tricarboxylic acid (TCA) pathway to supply the required energy to differentiate into the bone cells [9]. As a result, a higher OxPhos activity with an unaltered or decrease in glycolysis happens in MSCs differentiation [9,12,13].…”

Oxidative Stress in Cancer Cell Metabolism

“…Mesenchymal stromal cell (MSC) metabolism has the ability to modify cancer cell metabolism and alter malignancy by transferring mitochondria and/or mitochondrial DNA (mt DNA) to cancer cells thereby increasing mitochondrial content and enhance oxidative phosphorylation (OXPHOS) to favor proliferation and invasion [ 143 ]. The stromal metabolism by the cancer-associated fibroblasts produces high-energy nutrients (such as lactate and ketones) that act as fuels for mitochondrial biogenesis [ 6 ].…”

Mesenchymal Stromal Cell-Derived Extracellular Vesicles Regulate the Mitochondrial Metabolism via Transfer of miRNAs

“…Mitochondrial transfer mechanisms between MSCs and recipient cells are based on cell fusion, EV secretion, gap junctions or tunnelling nanotubes ( 48 ). In the acute phase of lung injury, internalized mitochondria were shown to increase ATP concentration in recipient cells, leading to bioenergetics restoration and cell protection ( 49 ).…”

“…MSC mitochondrial transfer plays multiple roles, including tissue repair during injuries, apoptosis prevention in endothelial cells during ischemic stress or metabolic reprogramming ( 50 , 51 ). Horizontal transfer of mitochondria or mitochondrial DNA between cells address therapeutic applications in MSCs regenerative medicine ( 48 ).…”