Mesenchymal stromal cells, metabolism, and mitochondrial transfer in bone marrow normal and malignant hematopoiesis

Abstract

Hematopoietic stem cell (HSC) transplantation-based treatments are in different phases of clinical development, ranging from current therapies to a promise in the repair and regeneration of diseased tissues and organs. Mesenchymal stromal/stem cells (MSCs), which are fibroblast-like heterogeneous progenitors with multilineage differentiation (osteogenic, chondrogenic, and adipogenic) and self-renewal potential, and exist in the bone marrow (BM), adipose, and synovium, among other tissues, represent one of the most widely used sources of stem cells in regenerative medicine. MSCs derived from bone marrow (BM-MSCs) exhibit a variety of traits, including the potential to drive HSC fate and anti-inflammatory and immunosuppressive capabilities via paracrine activities and interactions with the innate and adaptive immune systems. The role of BM-MSC-derived adipocytes is more controversial and may act as positive or negative regulators of benign or malignant hematopoiesis based on their anatomical location and functional crosstalk with surrounding cells in the BM microenvironment. This review highlights the most recent clinical and pre-clinical findings on how BM-MSCs interact with the surrounding HSCs, progenitors, and immune cells, and address some recent insights on the mechanisms that mediate MSCs and adipocyte metabolic control through a metabolic crosstalk between BM microenvironment cells and intercellular mitochondrial transfer in normal and malignant hematopoiesis.

Keywords: adipocytes; bone marrow; hematological malignancies; hematopoiesis; mesenchymal stem cells; metabolism; mitochondrial transfer.

FIGURE 1

Schematic representation of mitochondria transfer mechanisms between BM-MSCs and HSCs in response to blood formation emergencies. Intercellular mitochondrial exchange between BM-MSCs and HSPCs occurs through (1) tunneling nano-tubules (TNTs) via stabilization of cytoskeleton element (F-actin, myosin, and tubulin) and membrane adapter proteins (miro1/2); (2) gap junction (GJ) channels such as connexin 43 (Cx43), where two juxtapositioned connexin hemichannels form pores connecting two neighboring cells, facilitating bidirectional mitochondrial exchange; and (3) extracellular vesicles ranging from 0.1 to 1 μm formed by blebbing of the plasma membrane. Different stress signals differentially regulate the intercellular mitochondrial exchange between MSCs and HSCs to improve the hematopoietic outcome. Following myeloablative irradiation and HSPC transplantation, transplanted HSPCs transfer functional mitochondria to BM-MSC via the gap junction protein connexin 43 in a cell contact-dependent manner, enhances MSC metabolic recovery, ATP levels, and proliferation, which, in turn, by regulating the BM niche factors (CXCL12, SCF, IL-7, osteopontin, and angiopoietin-1) improves HSPC proliferation/survival. By contrast, in infection stress hematopoiesis, BM-MSCs facilitate the transfer of mitochondria to HSPCs via TNTs and/or Cx43 GJ, improve HSPC metabolism by switching from glycolysis to oxidative phosphorylation, and subsequently stimulate hematopoietic recovery. Exogeneous-isolated functional mitochondria can be efficiently transferred into HSPCs through macropicnocytosis/endocytosis. These transferred mitochondria metabolically upgrade HSPC and boost long-term engraftment potential. ATP, adenosine triphosphate; Miro1/2, mitochondrial RhoGTPase 1/2; mito, mitochondria.

FIGURE 2

Different modes of BM-MSC crosstalk with leukemic cells. (1) Mitochondrial transfer: leukemic cell interaction converts the BM-MSCs into cancer-associated fibroblasts (CAFs) with altered features to support leukemia. Mitochondrial transfer from MSCs to leukemic cells occurs through tunneling nanotubes (TnTs), gap junctions (GJs), or via mitochondria carrying extracellular vesicles (EVs). (2) Adipogenic induction: these CAFs are biased toward adipocyte production with reduced osteoblast differentiation. Adipocytes support leukemia progression by secreting inflammatory cytokines and lipid molecules like free fatty acid (FFA) and monounsaturated fatty acids (MUFA) for cell growth and proliferation. (3) Metabolic symbiosis: the BM stromal cells supply different metabolites like lactate to maintain OXPHOS and amino acids like asparagine and glutamine (also citrulline), for biosynthetic needs of leukemic cells. (4) Chemoresistance: BM-MSCs also provide chemoresistance by providing cysteine for glutathione (GSH) synthesis. They also induce aldehyde dehydrogenase (ALDH) and glutathione peroxidase (GPX) in leukemic cells to metabolize chemotherapeutic drugs and reduce their effects.