Mitochondrial reactive oxygen species regulate adipocyte differentiation of mesenchymal stem cells in hematopoietic stress induced by arabinosylcytosine.

Weimin Wang,Yao Zhang,Kaiyan Liu,Wenyi Lu,Gabriele Saretzki

doi:10.1371/journal.pone.0120629

Weimin Wang, Yao Zhang + Show 3 more

Open Access

https://doi.org/10.1371/journal.pone.0120629

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Journal: PloS one	Publication Date: Mar 13, 2015
Citations: 73	License type: CC BY 4.0

Affiliation: Peking University People's Hospital, Peking University

Abstract

ObjectiveThe increase in adipocytes induced by chemotherapeutic drugs may play a negative role in hematopoietic recovery. However, the mechanism underlying adipocyte differentiation of mesenchymal stem cells (MSCs) in hematopoietic stress is still unknown. Hence, the involvement of reactive oxygen species (ROS) in adipocyte differentiation under hematopoietic stress was investigated in vitro and in vivo.MethodsThe roles of cellular ROS in adipogenesis were investigated in vivo through an adipocyte hyperplasia marrow model under hematopoietic stress induced by arabinosylcytosine (Ara-C) and in vitro via adipocyte differentiation of human MSCs. ROS levels were detected using the CM-H2DCFDA probe and Mito-SOX dye. Adipogenesis was evaluated by histopathology and oil red O staining, whereas detection of mRNA levels of antioxidant enzymes and adipogenesis markers was performed using quantitative real-time polymerase chain reaction analysis.ResultsROS were found to play an important role in regulating adipocyte differentiation of MSCs by activating peroxisome proliferator-activated receptor gamma (PPARγ,) while the antioxidant N-acetyl-L-cysteine acts through ROS to inhibit adipocyte differentiation. The elevated ROS levels induced by Ara-C were caused by both over-generation of mitochondrial ROS and reduction of antioxidant enzymes (Cu/Zn Superoxide dismutase and catalase). Our findings suggest that a mitochondrial-targeted antioxidant could diminish adipocyte differentiation.

Highlights

Long-term chemotherapy and hematopoietic stem cell transplantation (HSCT) are effective treatments for hematologic malignancies
reactive oxygen species (ROS) were found to play an important role in regulating adipocyte differentiation of mesenchymal stem cells (MSCs) by activating peroxisome proliferator-activated receptor gamma (PPARγ,) while the antioxidant N-acetyl-L-cysteine acts through ROS to inhibit adipocyte differentiation
The increase in adipocytes induced by chemotherapeutic drugs may play a negative role in hematopoietic recovery following chemotherapy and HSCT

Summary

Introduction

Long-term chemotherapy and hematopoietic stem cell transplantation (HSCT) are effective treatments for hematologic malignancies. In addition to hematopoietic stem cells (HSCs), the bone marrow (BM) hematopoietic microenvironment, which represents an important niche for HSCs, has been reported to be impaired after long-term chemotherapy and HSCT [2,3,4,5,6]. 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]. The increase in adipocytes induced by chemotherapeutic drugs may play a negative role in hematopoietic recovery following chemotherapy and HSCT. Further understanding of the mechanism underlying adipocyte differentiation from MSCs might facilitate the cognition of adipogenesis induced by chemotherapy

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Conclusion