Connexin-43 in the osteogenic BM niche regulates its cellular composition and the bidirectional traffic of hematopoietic stem cells and progenitors

Abstract

Connexin-43 (Cx43), a gap junction protein involved in control of cell proliferation, differentiation and migration, has been suggested to have a role in hematopoiesis. Cx43 is highly expressed in osteoblasts and osteogenic progenitors (OB/P). To elucidate the biologic function of Cx43 in the hematopoietic microenvironment (HM) and its influence in hematopoietic stem cell (HSC) activity, we studied the hematopoietic function in an IntroductionIn the adult bone marrow (BM), the hematopoietic function is supported by the proliferation and differentiation of a finite number of transplantable hematopoietic stem cells and progenitors (HSCs/Ps) that have self-renewal and multipotential differentiation capacity. Endosteal and neighboring vascular/perivascular niches have been proposed as anatomic sites that control HSC/P activity, providing signals that regulate the stem cell pool size, survival, and migration. [1][2][3][4] The definition of the cell components of the BM hematopoietic microenvironment (HM) is an area of debate. Endothelial cells, 2 mesenchymal stem cells (MSCs), 5 and osteoblasts and osteogenic progenitors (OB/Ps) 1,4,6 represent major cell components of the BM HM.A poorly studied mechanism of intercellular communication (IC) in the HM is mediated by gap junction (GJ) channels. GJ channels are formed by a large family of proteins called connexins (Cxs). Each neighboring cell contributes cell-to-cell channels with 1 hemichannel that dock head-to-head. GJ channels have the ability to transfer ions and low-molecular weight secondary messengers from one cell to another depending on concentration gradients and Cx-dependent selective permeability. 7 Connexin-43 (Cx43), one member of this protein family, is highly expressed by adult BM stromal cells, 8 osteoblasts, 9 endothelial cells, 2 and MSCs, 5 and is also expressed by HSCs. 10 The presence of a functional Cx43-dependence of GJIC between osteoblasts and stromal cells, as well as between stromal cells and HSCs, has been confirmed in vitro. 11 After HSC transplantation, HSCs must first home to the BM, and then localize and anchor in suitable microenvironments within the BM, a process known as lodgment. 12 This process involves the migration of HSC/Ps through different layers of cell components in the HM, including endothelial cells and mesenchymal-origin cells, which act as extrinsic HSC/P migration regulators, 13 and is directed by chemokine gradients. Myeloablation through irradiation has been postulated to modify the functional ability of the BM HM to allow HSC homing and retention through clearance of HSC niches. 14 The effect of irradiation on the BM HM is not well known, but diverse studies have shown that it is not innocuous 15 and includes the up-regulation of expression and secretion of Cxcl12 16 and the up-regulation of the expression of Cx43 in the BM. 17 It has been proposed that Cx43 hemichannels are important in reinforcing cell-to-cell migration and that Cx43-dependent GJ are needed in the process of neuronal migration during neocortex form...

Osteopontin attenuates aging‐associated phenotypes of hematopoietic stem cells

“…Cells were than stained with Differential Wright Giemsa stain, and then, colonies were enumerated based on size and morphology (Gonzalez‐Nieto et al , 2012). …”

Autonomic regulation of hematopoiesis and cancer

“…While one study has shown that BM stromal CXCL12 secretion requires electromechanical coupling by connexin-43 and -45, 24 another study has shown that connexin-43 deficiency increases BM stromal CXCL12 secretion but it compromises HSC homing and hematopoietic recovery upon myeloablation. 25 This is at least partly due to connexin-43-mediated transfer of high, damaging amounts of reactive oxygen species to the BM stroma, which would protect HSCs during stress hematopoiesis. 26 However, we noted that systemic activation of β-adrenergic receptors, e.g.…”

Regulation of hematopoiesis in endosteal microenvironments

“…The mechanism how osteocyte regulates osteoblast during G-CSF-induced mobilization is still unclear. Given the fact that conditional deletion of connexin-43 led to dysfunction of osteoblasts and mobilization defect by G-CSF [43], it is conceivable that contact communication through gap junction between osteocytes and endosteal niche cells might be involved in the mechanism of niche regulation.…”