Hematopoietic recovery following chemotherapy is improved by BADGE-induced inhibition of adipogenesis

Abstract

This study was designed to investigate the role of increased adipocytes in the bone marrow (BM) niche induced by high-dose chemotherapy in hematopoietic recovery. Arabinosylcytosine (Ara-C) was administered to adult C57BL/6J mice to induce adipogenesis in the BM. We investigated the effects of adipogenesis on hematopoietic recovery following chemotherapy, using the peroxisome proliferator-activated receptor gamma inhibitor, bisphenol A diglycidyl ether (BADGE). Adipocyte hyperplasia could be induced by Ara-C treatment in BM and inhibited by BADGE. The accelerated recovery of leukocyte counts, increased colony forming units, and a higher proportion of Ki67(+)CD45(+) BM cells and Ki67(+)Lin(-)Sca1(+)c-kit(+) hematopoietic stem cells were observed in the long bone marrow of adipocyte-inhibited mice, as well as an increase in the number of CD45(+) BM cells in the tail fatty marrow compared to controls. Adipocytes participated in creating a distinctive niche for hematopoietic cells. In addition, lower expression of stromal cell-derived factor-1α and hypoxia-inducible factor-1 alpha were detected in the BADGE-treated group. These results indicate that hematopoietic recovery is improved following chemotherapy in adipogenesis-inhibited mice. In addition, adipocytes may create an individual niche that affects the proliferation and migration of hematopoietic cells in vitro and in vivo.

Mitochondrial Reactive Oxygen Species Regulate Adipocyte Differentiation of Mesenchymal Stem Cells in Hematopoietic Stress Induced by Arabinosylcytosine

“…Our group has previously investigated adipogenesis induced by Ara-C and the effect of PPARγ inhibitor on hematopoietic recovery after chemotherapy [9]. As ROS mediate adipocyte differentiation in vitro and adipocytes in BM are derived from the differentiation of MSCs, whether the antioxidant NAC diminishes adipogenesis induced by Ara-C treatment was further examined in the current study.…”

“…Several studies have uncovered the role of adipocytes in actively suppressing hematopoiesis rather than passively filling the space of damaged BM [7,8]. In addition, previous studies by our research group have demonstrated that adipocyte hyperplasia can be induced by arabinosylcytosine (Ara-C) treatment, while bisphenol A diglycidyl ether (BADGE), a peroxisome proliferator-activated receptor gamma inhibitor), contributes to improved hematopoietic recovery after chemotherapy by inhibiting adipogenesis [9]. Therefore, the increase in adipocytes induced by chemotherapeutic drugs may play a negative role in hematopoietic recovery following chemotherapy and HSCT.…”

Inhibition of adipogenic differentiation of bone marrow mesenchymal stem cells by erythropoietin via activating ERK and P38 MAPK

“…Naveiras et al (2009) demonstrated that fat cells in the bone marrow can negatively regulate hematopoietic stem cells. The presence of a number of fat cells in the bone marrow can inhibit hematopoietic reconstruction of hematopoietic stem cells after transplantation, while inhibition of mouse marrow fat after chemotherapy can promote hematopoietic recovery (Zhu et al, 2013). In contrast, chronic blood loss in premenopausal women can stimulate marrow hematopoiesis, while marrow fat diseases such as osteoporosis typically develop in postmenopausal women (Gurevitch et al, 1999), indicating that marrow hematopoiesis in the body may also respond to the bone marrow microenvironment.…”

Niche heterogeneity in the bone marrow

“…69,140 Hematopoietic recovery is improved following chemotherapy in mice with chemically inhibited adipogenesis. 141 In mouse tail vertebrae, where BM cavities are densely filled with adipocytes, the few HSCs detected are largely quiescent. 136 The adipocyte suppressive function has been attributed to the reduced production of granulocyte colony-stimulating factors (GM-CSF and G-CSF) and to the increased secretion of lipocalin-2 and neuropilin.…”