Gap Junctions in the Bone Marrow Lympho-Hematopoietic Stem Cell Niche, Leukemia Progression, and Chemoresistance

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.

The CAR group of Ig cell adhesion proteins–Regulators of gap junctions?

“…However, cross‐talk between hematopoietic and bone marrow cells via gap junctions appear to be important during hematopoietic stem cell differentiation. [ 77 ] Again, here it is noteworthy to mention that connexin43 – like ESAM – is critical for hematopoietic reconstitution under 5‐fluorouracil induced stress hematopoiesis which resulted in an attenuated recovery of blood cells. [ 78,79 ] Future studies are needed to test whether mutation of ESAM has an effect on connexin expression and or function during hematopoiesis.…”

Mitochondria at Work: New Insights into Regulation and Dysregulation of Cellular Energy Supply and Metabolism

“…Such transfer was cell-contact dependent and mediated by HSPC connexin-43 (Cx43) [ 134 ]. These results demonstrate that HSPC transfer not only reconstitutes the hematopoietic system following transplantation, but also supports and induces the metabolic recovery of irradiation-damaged microenvironment via mitochondria transfer [ 131 , 132 , 133 , 134 ].…”

“…Connexin Gap junction channels (GJ) exert cell-intrinsic and cell-extrinsic effects on HSC and BM stromal cells. They control the transfer of ions, small metabolites, and organelles to adjacent cells [ 132 ]. Recent findings reveal a novel function of mitochondria in directly contributing to cellular reprogramming [ 133 ].…”

Mek1 and Mek2 Functional Redundancy in Erythropoiesis

“…HSCs generate mature leukocytes through successive differentiation steps of increasingly committed HSC progenitors ( Freitas et al, 2017 ; Zhang et al, 2018 ; Singh and Cancelas, 2020 ). To determine whether impaired HSC maturation contributed to the 1 Mek1 phenotype, global hematopoietic development was assessed in controls and 1 Mek1 mice following the gating strategy described in Supplementary Figure 1 ( Freitas et al, 2017 ).…”