Hematopoietic Stem/Progenitor Cells Express Functional Mitochondrial Energy-Dependent Cystic Fibrosis Transmembrane Conductance Regulator

Abstract

Bone marrow-derived hematopoietic stem/progenitor cells (HSPCs) encompass a wide array of cell subsets with different capacities of engraftment and injured tissue-regenerating potential. The characterization/ isolation of the stem cell subpopulations represents a major challenge to improve the efficacy of transplantation protocols used in regenerative medicine. Cystic fibrosis (CF) is one of the diseases whose hope of cure relies on the successful application of cell-based gene therapy. This study was aimed at characterizing murine HSPCs on the basis of their bioenergetic competence and CF transmembrane conductance regulator (CFTR) expression. Positively immunoselected Sca-1 + HSPCs encompassed 2 populations distinguished by their different size, Sca-1 expression and mitochondrial content. The smaller were the cells, the higher was Sca-1 expression and the lower was the intracellular density of functional mitochondria. Reverse transcriptionpolymerase chain reaction and western blotting revealed that HSPCs expressed CFTR mRNA and protein, which was also functional, as assessed by spectrofluorimetric and patch-clamp techniques. Inhibition of mitochondrial oxidative phosphorylation by oligomycin resulted in a 70% decrease of both the intracelluar adenosine triphosphate content and CFTR-mediated channel activity. Finally, HSPCs with lower Sca-1 expression and higher mitochondrial content displayed higher CFTR levels. Our findings identify 2 subpopulations in HSPCs and unveil a so-far unappreciated relationship between bioenergetic metabolism and CFTR in HSPC biology.

Effect of Acute Lung Injury on VLA-4 and CXCR4 Expression in Resident and Circulating Hematopoietic Stem/Progenitor Cells

“…We have previously shown that the Sca-1 + population in naïve mice is comprised of two subpopulations, one smaller and one bigger, according to their physical parameters [23]. These two subsets were further analyzed for CD49d expression in the context of LPS-induced inflammation.…”

“…We have previously shown that resident HSPCs are comprised of two subsets as determined by physical parameters and mitochondrial content [23]. R1 (bigger) cells are less primitive in that they display higher levels of mitochondria, as also shown in human CD34 + cells [56].…”

Paracrine Effects and Heterogeneity of Marrow-Derived Stem/Progenitor Cells: Relevance for the Treatment of Respiratory Diseases

“…Even in functionally identified stem cell populations, cellular and molecular properties and behavior vary [Lemischka et al, 1986;Dykstra et al, 2007]. We [Piro et al, 2012;Trotta et al, 2013] and others [Kucia et al, 2008;Wong et al, 2009;Ratajczak et al, 2011] have identified HSPC subpopulations on the basis of immunophenotyping. It is not known whether these subpopulations are endowed with different engraftment capacity in the lung, although recent work points to this possibility [Wong et al, 2009].…”

CFTR‐dependent chloride efflux in cystic fibrosis mononuclear cells is increased by ivacaftor therapy

“…types, including hematopoietic stem cells 15,16 and differentiated cells ensuing from them. 17 Of note, CFTR protein expression on neutrophil membranes, secretory vesicles, and phagocytic vacuoles, 18,19 and in MNC 20,21 and macrophages 22 has been described.…”

“…Besides epithelial cells, CFTR expression has been shown in other cell types, including hematopoietic stem cells and differentiated cells ensuing from them and in MNC and macrophages has been described.…”