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. 2020 Jan 25;21(3):796. doi: 10.3390/ijms21030796

Figure 3.

Figure 3

Schematic representation of normal and leukemic hematopoiesis. (A) Connexin (Cx) is expressed by hematopoietic stem and progenitor cells (HSPC) and bone marrow (BM) stromal cells. Gap junctions comprised of Cx43/45 between osteoblasts regulates CXCL12 secretion and HSC behavior within the niche. During myeloablation, Cx43 protects HSC from reactive oxygen species (ROS) induced damage by ROS scavenging through pseudosyncytial coupling of BM stromal cells. Cx43 mediated mitochondria transfer from BM stromal cells to HSPC regulates the emergency granulopoiesis and alleviates inflammation. Angiopoietin-1(Ang-1)/Tie2 and thrombopoietin (TPO)/MPL signaling maintains HSC quiescence. (B) Expression of Cx43 increased in leukemia initiating cells (LIC)/blast cells as well as in the surrounding BM niche cells. Leukemic cells receive signals from the BM microenvironment through diffusible paracrine factors (cytokines, chemokines, and metabolites) and/or by plasma-membrane fusion with tunneling nanotubes (TNT) or extracellular vesicles (EV). The higher expression of Cx43 in the leukemic environment by promoting the exchange of survival factors facilitates the proliferation and survival of malignant cells. High oxidative stress in leukemic cells further increases ROS levels in BM stromal cells and induces the transfer of mitochondria from stromal cells to LIC cells/blast cells through TNT and/or EV, while tumor cell CD38 promotes TNT formation. Transferred functional mitochondria regulate leukemic cells’ bioenergetics and metabolism, and are associated with leukemogenesis and chemoresistance. Although expression of connexins regulates TNT formation, their role in TNT assembly and organelle trafficking in the leukemic environment remains to be determined. BM stromal cells by modulating the TPO/MPL, Ang-1/Tie2, and CXCR4-CXCL12 pathways protect leukemic cells from chemotherapy. Blue arrow indicates increased expression in leukemia as compared to normal hematopoiesis. EC-endothelial cells. HSC:-Hematopoietic stem cells. MSC:-Mesenchymal stem cells, OXPHOS: Oxidative phosphorylation.