Abstract
The crosstalk between hematopoietic stem cells (HSC) and bone marrow (BM) microenvironment is critical for homeostasis and hematopoietic regeneration in response to blood formation emergencies after injury, and has been associated with leukemia transformation and progression. Intercellular signals by the BM stromal cells in the form of cell-bound or secreted factors, or by physical interaction, regulate HSC localization, maintenance, and differentiation within increasingly defined BM HSC niches. Gap junctions (GJ) are comprised of arrays of membrane embedded channels formed by connexin proteins, and control crucial signaling functions, including the transfer of ions, small metabolites, and organelles to adjacent cells which affect intracellular mechanisms of signaling and autophagy. This review will discuss the role of GJ in both normal and leukemic hematopoiesis, and highlight some of the most novel approaches that may improve the efficacy of cytotoxic drugs. Connexin GJ channels exert both cell-intrinsic and cell-extrinsic effects on HSC and BM stromal cells, involved in regenerative hematopoiesis after myelosuppression, and represent an alternative system of cell communication through a combination of electrical and metabolic coupling as well as organelle transfer in the HSC niche. GJ intercellular communication (GJIC) in the HSC niche improves cellular bioenergetics, and rejuvenates damaged recipient cells. Unfortunately, they can also support leukemia proliferation and survival by creating leukemic niches that provide GJIC dependent energy sources and facilitate chemoresistance and relapse. The emergence of new strategies to disrupt self-reinforcing malignant niches and intercellular organelle exchange in leukemic niches, while at the same time conserving normal hematopoietic GJIC function, could synergize the effect of chemotherapy drugs in eradicating minimal residual disease. An improved understanding of the molecular basis of connexin regulation in normal and leukemic hematopoiesis is warranted for the re-establishment of normal hematopoiesis after chemotherapy.
Highlights
Lifelong production of blood cells and the robust regenerative capacity of lympho-hematopoiesis depend on hematopoietic stem cell (HSC) self-renewal, proliferation, and differentiation
While we have advanced our understanding of the life-cycle of connexins and Gap junctions (GJ), there is consensus that certain processes are especially relevant in specific cell types where the subcellular localization of connexins and GJ intercellular communication (GJIC) may result in function specialization and specific secondary messenger gating, cell adhesion, scaffolding, or activation of context-dependent signalomes, that are relevant in health and disease
The emergence of new pharmacological and molecular approaches targeting the depletion of intercellular organelle exchange could be of particular clinical interest in leukemia treatment, and they could synergize the effect of chemotherapy drugs in eradicating minimal residual disease after chemotherapy
Summary
Lifelong production of blood cells and the robust regenerative capacity of lympho-hematopoiesis depend on hematopoietic stem cell (HSC) self-renewal, proliferation, and differentiation. A growing body of work has detailed the importance of GJ mediated intercellular communication (GJIC) in the regulation of signaling pathways required for HSC survival, proliferation, and fate decisions [8,14,15,16,17,18] Niche environment regulates both normal and malignant hematopoiesis by offering needed nutrients. Many connexins are expressed at the mRNA level, the protein expression may not reach functional levels in specific types of cells This is especially important in BM hematopoiesis where the state of activation and/or differentiation of cell subtypes is highly dependent on the level of expression and/or function of connexins [15,17,28,29,30,31,32]. While we have advanced our understanding of the life-cycle of connexins and GJ, there is consensus that certain processes are especially relevant in specific cell types where the subcellular localization of connexins and GJIC may result in function specialization and specific secondary messenger gating, cell adhesion, scaffolding, or activation of context-dependent signalomes, that are relevant in health and disease
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