Int J Biol Sci 2022; 18(5):2091-2103. doi:10.7150/ijbs.63876 This issue

Research Paper

Specific overexpression of SIRT1 in mesenchymal stem cells rescues hematopoiesis niche in BMI1 knockout mice through promoting CXCL12 expression

Jinbo Li, Ph.D.1,2✉, Xing Li, M.D.5, Wen Sun, Ph.D.4, Jiao Zhang, M.S.2, Quanquan Yan, M.S.2, Jun Wu, Ph.D.6, Jianliang Jin, Ph.D.6, Ruinan Lu, M.D.7, Dengshun Miao, M.D., Ph.D.2,3✉

1. Department of Pharmacology, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, Hebei 050011, China
2. State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, China
3. Department of Plastic Surgery, The Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
4. Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu 210029, China
5. Department of Immuno-oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, China
6. Department of Human Anatomy, Nanjing Medical University, Nanjing, Jiangsu 210029, China
7. Department of Hematology, Jiangsu People's Hospital, Nanjing, Jiangsu 210029, China

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Citation:
Li J, Li X, Sun W, Zhang J, Yan Q, Wu J, Jin J, Lu R, Miao D. Specific overexpression of SIRT1 in mesenchymal stem cells rescues hematopoiesis niche in BMI1 knockout mice through promoting CXCL12 expression. Int J Biol Sci 2022; 18(5):2091-2103. doi:10.7150/ijbs.63876. Available from https://www.ijbs.com/v18p2091.htm

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Abstract

Graphic abstract

Osteoblastic lineage cells (OBCs) are bone-building cells and essential component of hematopoietic niche, but mechanisms whereby bone-building and hematopoiesis-supportive activities of OBCs could be regulated simultaneously remain largely unknown. Here we found that B cell-specific Moloney murine leukemia virus integration site 1 (Bmi1) was involved in such a co-regulatory mechanism. In this study, we first found that, accompanied with marked decline of osteogenic activity, the hematopoietic niche in Bmi1 knockout (KO) mice was severely impaired and manifested as CXCL12 expression falls and LSK homing failure; however, intratibial injection with CXCL12 effectively facilitated LSK accumulation in bone marrow of Bmi1 KO mice. To try to rescue these defects in Bmi1 KO mice, we generated Bmi1KO/Sirt1Tg (KO-TG) double mutant mice with Sirt1 specific overexpression in mesenchymal progenitor cells (MPCs) in Bmi1 KO mice, and our data showed that KO-TG mice had significantly increased bone-building activity, elevated Cxcl12 expression by MPCs, increased LSK homing and expanded LSK pool in bone marrow compared to Bmi1 KO mice. Of note, similar improvements in KO-TG mice were observed in Bmi1 KO mice fed with dietary resveratrol, an established Sirt1 activator, comparing with KO control mice. Therefore, pharmacologic activation of Bmi1/Sirt1 signaling pathway could simultaneously promote bone-building and hematopoiesis-supportive activities of OBCs.

Keywords: mesenchymal progenitor cells, hematopoietic stem cell niche, Bmi1, Sirt1, CXCL12.