Irradiation Haematopoiesis Recovery Orchestrated by IL-12/IL-12Rβ1/TYK2/STAT3-Initiated Osteogenic Differentiation of Mouse Bone Marrow-Derived Mesenchymal Stem Cells.

Fengjie Li,Li Chen,Rong Zhang,Yang Xiang,Yang Yang,Lixin Xiang,Shengwen Calvin Li,Gang Zhang,Zhongjun Li,Changpeng Hu,Qian Ran

doi:10.3389/fcell.2021.729293

Abstract

PurposeRepairing the irradiation-induced osteogenic differentiation injury of bone marrow mesenchymal stem cells (BM-MSCs) is beneficial to recovering haematopoiesis injury in radiotherapy; however, its mechanism is elusive. Our study aimed to help meet the needs of understanding the effects of radiotherapy on BM-MSC osteogenic potential.Methods and MaterialsBalb/c mice and the BM-MSCs were used to evaluate the irradiation-induced osteogenic differentiation injury in vivo. The cellular and molecular characterization were applied to determine the mechanism for recovery of irradiation-derived haematopoiesis injuries.ResultsWe report a functional role of IL-12 in acute irradiation hematopoietic injury recovery and intend to dissect the possible mechanisms through BM-MSC, other than the direct effect of IL-12 on hematopoietic stem and progenitor cells (HSPCs). Specifically, we show that early use of IL-12 enhanced the osteogenic differentiation of BM-MSCs through IL-12Rβ1/TYK2/STAT3 signaling; furthermore, IL-12 induced osteogenesis facilitated bone formation and irradiation hematopoiesis recovery when transplanted BM-MSCs in the femur of Balb/c mice. For the mechanism of action, we found that IL-12 receptor beta 1 (IL-12Rβ1) expression of irradiated BM-MSCs was upregulated rapidly, coincidentally consistent with early use of IL-12 induced osteogenic differentiation enhancement. IL-12Rβ1 and tyrosine kinase 2 gene (Tyk2) silencing experiments and phosphotyrosine of signal transducer and activator of transcription 3 (p-STAT3) suppression experiments indicated the IL-12Rβ1/TYK2/STAT3 signaling was essential in IL-12-induced osteogenic differentiation enhancement of BM-MSCs.ConclusionThese findings suggested that IL-12 may exert BM-MSCs-based hematopoietic recovery by repairing osteogenic differentiation abilities damages through IL-12Rβ1/TYK2/STAT3 signaling pathway post-irradiation.

Highlights

Radiotherapy is considered one of the most accepted and widely used medical treatments for tumors and cancers
We show that early use of IL-12 enhanced the osteogenic differentiation of bone marrow mesenchymal stem cells (BM-MSCs) through IL-12Rβ1/TYK2/STAT3 signaling; IL-12 induced osteogenesis facilitated bone formation and irradiation hematopoiesis recovery when transplanted BM-MSCs in the femur of Balb/c mice
For the mechanism of action, we found that IL-12 receptor beta 1 (IL-12Rβ1) expression of irradiated BM-MSCs was upregulated rapidly, coincidentally consistent with early use of IL-12 induced osteogenic differentiation enhancement

Summary

Introduction

Radiotherapy is considered one of the most accepted and widely used medical treatments for tumors and cancers. Irradiation causes myelosuppression and hematopoietic injuries, typical side effects, and patient radiotherapy obstacles (Greenberger and Epperly, 2009; Xu et al, 2011; Zhang et al, 2015; Seshadri and Qu, 2016; Zhao and Liu, 2016). No long-term survivors have been reported in those who received current HSCT for severe irradiation damage of the bone marrow, even their temporary autologous blood cell recovery was observed. In such cases, the causes of death involved a wide potential exacerbation of hematopoietic and non-hematopoietic tissue injuries caused by the conditioning irradiation pretreatment. Preserving and promoting HM biologic function became the target of hematopoietic reconstitution and rescuing hematopoietic injury (Moore, 2004; Greenberger and Epperly, 2009; Seshadri and Qu, 2016)

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Conclusion