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

  • Front Cell Dev Biol. 2021 Sep 3:9:729293. doi: 10.3389/fcell.2021.729293.
Fengjie Li  1 ,  Rong Zhang  2 ,  Changpeng Hu  2 ,  Qian Ran  1 ,  Yang Xiang  1 ,  Lixin Xiang  1 ,  Li Chen  1 ,  Yang Yang  1 ,  Shengwen Calvin Li  3 ,  Gang Zhang  4 ,  Zhongjun Li  1
Affiliations
  • 1. Department of Blood Transfusion, The Irradiation Biology Laboratory, The Second Affiliated Hospital, The Third Military Medical University, Chongqing, China.
  • 2. Department of Pharmacy, The Second Affiliated Hospital, The Third Military Medical University, Chongqing, China.
  • 3. CHOC Children's Research Institute, Children's Hospital of Orange County, University of California, Irvine, Irvine, CA, United States.
  • 4. Department of Oral and Maxillofacial Surgery, The Second Affiliated Hospital, The Third Military Medical University, Chongqing, China.
PMID: 34540843 DOI: 10.3389/fcell.2021.729293
Abstract

Purpose: Repairing 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 materials: Balb/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.

Results: We 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.

Conclusion: These 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.

Keywords
IL-12; haematopoiesis; irradiation; osteogenesis; recovery.
Products