한빛사논문
- 조회729
Dong Suk Yoon1†, Yoorim Choi2†, Kyoung‑Mi Lee2†, Eun Ae Ko2, Eun‑Ji Kim2,3, Kwang Hwan Park2 and Jin Woo Lee2,3*
1Department of Biomedical Science, Hwasung Medi-Science University, Hwaseong‑Si 18274, Gyeonggi‑Do, South Korea.
2Department of Orthopaedic Surgery, Yonsei University College of Medicine, Seoul 03722, South Korea.
3Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, South Korea.
†Dong Suk Yoon, Yoorim Choi and Kyoung-Mi Lee contributed equally to this work
*Correspondence: Jin Woo Lee
Abstract
Background
Although mRNA dysregulation can induce changes in mesenchymal stem cell (MSC) homeostasis, the mechanisms by which post-transcriptional regulation influences MSC differentiation potential remain understudied. PUMILIO2 (PUM2) represses translation by binding target mRNAs in a sequence-specific manner.
Methods
In vitro osteogenic differentiation assays were conducted using human bone marrow-derived MSCs. Alkaline phosphatase and alizarin red S staining were used to evaluate the osteogenic potential of MSCs. A rat xenograft model featuring a calvarial defect to examine effects of MSC-driven bone regeneration. RNA-immunoprecipitation (RNA-IP) assay was used to determine the interaction between PUM2 protein and Distal-Less Homeobox 5 (DLX5) mRNA. Ovariectomized (OVX) mice were employed to evaluate the effect of gene therapy for postmenopausal osteoporosis.
Results
Here, we elucidated the molecular mechanism of PUM2 in MSC osteogenesis and evaluated the applicability of PUM2 knockdown (KD) as a potential cell-based or gene therapy. PUM2 level was downregulated during MSC osteogenic differentiation, and PUM2 KD enhanced MSC osteogenic potential. Following PUM2 KD, MSCs were transplanted onto calvarial defects in 12-week-old rats; after 8 weeks, transplanted MSCs promoted bone regeneration. PUM2 KD upregulated the expression of DLX5 mRNA and protein and the reporter activity of its 3'-untranslated region. RNA-IP revealed direct binding of PUM2 to DLX5 mRNA. We then evaluated the potential of adeno-associated virus serotype 9 (AAV9)-siPum2 as a gene therapy for osteoporosis in OVX mice.
Conclusion
Our findings suggest a novel role for PUM2 in MSC osteogenesis and highlight the potential of PUM2 KD-MSCs in bone regeneration. Additionally, we showed that AAV9-siPum2 is a potential gene therapy for osteoporosis.
논문정보
- Research article
- 2023년 04월 (BRIC 등록일 2023-04-24)
- 국내 연구진
- 의약학 > 재생의학
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