Transforming growth factor‐β boosts the functionality of human bone marrow‐derived mesenchymal stromal cells

Abstract

Transforming growth factor β1 (TGFβ1) is a negative regulator of hematopoiesis, and yet, it is frequently found at the active sites of hematopoiesis. Here, we show for the first time that bone marrow-derived mononuclear cells (BM MNCs) secrete TGFβ1 in response to erythropoietin (EPO). We further show that human bone marrow-derived mesenchymal stromal cells (BMSCs) briefly exposed to the conditioned medium of EPOprimed MNCs, or purified TGFβ1, gain significantly increased hematopoiesis-supportive ability. Mechanistically, we show that this phenomenon involves TGFβ1-mediated activation of nitric oxide (NO) signalling pathway in the BMSCs. The data suggest that EPO-MNC-TGFβ1 could be one of the regulatory axes operative in the bone marrow microenvironment involved in maintaining the functionality of the resident BMSCs.

Erythropoietin-Mediated Secretion of Transforming Growth Factor β1 by Bone Marrow Mononuclear Cells is Negatively Regulated by Granulocytes via Secretion of Erythropoietin Receptors in the Milieu.

“…3A). As seen in our previous experiments [4], the EPO-primed undep MNCs showed a dose-dependent increase in the TGFβ1 secretion up to 2 IU/ml of EPO, but this level remained steady even when the EPO concentration was raised to 5 IU/ml. Interestingly, the CM of unprimed (0 IU/ml) CD15-dep MNCs contained a much higher level of TGFβ1, as compared to its undep-control counterpart (Fig.…”

“…EPO functions by binding to and activating its cognate receptor, EPO-R, though non-EPO-Rmediated actions have also been reported [21]. We have recently demonstrated that BM MNCs secrete copious amounts of TGFβ1 when primed with EPO [4]. A small amount of EPO is constitutively present in the circulation (5 pM; ∼20 mU/mL; 100 pg/mL), and its level increases in response to hypoxia [22], hence it is logical to assume that a natural in-built mechanism must be operative in vivo to control excessive production of TGFβ1 in response to elevated levels of EPO.…”

“…Our earlier study shows that soluble EPO-R interferes with the EMST by BM MNCs [4]. Hence, we hypothesized that perhaps CD15 + cells negatively regulate EMST by BM MNCs by secreting sEPO-R in the milieu.…”

“…Transforming Growth Factor beta 1 (TGFβ1) is a pleiotropic cytokine, acting positively and negatively depending on its concentration or the target cell involved [1,2,3]. Earlier, we have shown that it boosts the hematopoietic supportive ability of human mesenchymal stromal cells [MSCs;4]. It plays a vital role in maintaining the quiescence of hematopoietic stem cells [HSCs; 5,6].…”

“…Our previous study demonstrated that bone marrow mononuclear cells (BM MNCs) secrete TGFβ1 in response to EPO [4], partly explaining its presence at the active sites of hematopoiesis. In the present study, we endeavored to identify the cell type involved in the process.…”