Hematopoietic Stem/Progenitor Cells Express Myoglobin and Neuroglobin: Adaptation to Hypoxia or Prevention from Oxidative Stress?

Abstract

Oxidative metabolism and redox signaling prove to play a decisional role in controlling adult hematopoietic stem/progenitor cells (HSPCs) biology. However, HSPCs reside in a hypoxic bone marrow microenvironment raising the question of how oxygen metabolism might be ensued. In this study, we provide for the first time novel functional and molecular evidences that human HSPCs express myoglobin (Mb) at level comparable with that of a muscle-derived cell line. Optical spectroscopy and oxymetry enabled to estimate an O2-sensitive heme-containing protein content of approximately 180 ng globin per 10(6) HSPC and a P50 of approximately 3 µM O2. Noticeably, expression of Mb mainly occurs through a HIF-1-induced alternative transcript (Mb-V/Mb-N = 35 ± 15, p < .01). A search for other Mb-related globins unveiled significant expression of neuroglobin (Ngb) but not of cytoglobin. Confocal microscopy immune detection of Mb in HSPCs strikingly revealed nuclear localization in cell subsets expressing high level of CD34 (nuclear/cytoplasmic Mb ratios 1.40 ± 0.02 vs. 0.85 ± 0.05, p < .01) whereas Ngb was homogeneously distributed in all the HSPC population. Dual-color fluorescence flow cytometry indicated that while the Mb content was homogeneously distributed in all the HSPC subsets that of Ngb was twofold higher in more immature HSPC. Moreover, we show that HSPCs exhibit a hypoxic nitrite reductase activity releasing NO consistent with described noncanonical functions of globins. Our finding extends the notion that Mb and Ngb can be expressed in nonmuscle and non-neural contexts, respectively, and is suggestive of a differential role of Mb in HSPC in controlling oxidative metabolism at different stages of commitment.

More than hemoglobin - the unexpected diversity of globins in vertebrate red blood cells

“…This corresponds to recent results presented by D'Aprile et al. () who found expression of Mb and Ngb in adult human hematopoietic stem/progenitor cells. Another online human gene database (GeneCards, http://www.genecards.org) displays mRNA expression of Mb , Ngb , and Cygb in blood plasma (Rebhan et al.…”

The Distinct Gene Regulatory Network of Myoglobin in Prostate and Breast Cancer

“…At a minor level, transcripts starting at exon 4u were also detected, while MB transcripts initiated at the myocyte-active gene promoter were only found in minute amounts. These results were in full agreement with previously published quantitative data on MB splice variant amounts in MDA-MB468 breast cancer, DLD-1 colon cancer cells [ 21 ] and hematopoietic stem/progenitor cells [ 24 ]. By mining of epigenetic data (e.g.…”

Function and evolution of vertebrate globins

“…in hematopoietic stem cells (D'Aprile et al . ) and tumour tissue (Emara et al . ) have been proposed.…”

“…The relative intensity of expression in different regions of the mammalian brain is controversially discussed , Hundahl et al 2012b) and additional sites of ectopic Ngb expression, e.g. in hematopoietic stem cells (D'Aprile et al 2014) and tumour tissue (Emara et al 2014) have been proposed. We like to point out that rigorous quantitative studies of regional Ngb gene expression, including intracellular protein levels as a pivotal clue to understand its physiological function(s), are still missing.…”