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Background <p>p18<sup>INK4 C</sup> (CDKN2C, encoded by <i>p18</i><sup><i>INK4c</i></sup> or <i>Cdkn2c</i>) is an early G1-phase cyclin-dependent kinase inhibitor protein. Previous studies demonstrated enhanced self-renewal capacity of hematopoietic stem cells (HSCs) in <i>p18</i><sup><i>−/−</i></sup> mice compared to wild-type (WT) mice. Given the critical role of bone marrow niche cells-particularly mesenchymal stromal cells (MSCs)-in hematopoiesis, this study investigated the functional alterations of <i>p18</i><sup><i>−/−</i></sup> MSCs and their impact on hematopoietic support.</p> Methods <p>Bone marrow derived MSCs were isolated from <i>p18</i><sup>−/−</sup> and WT mice. Their proliferation and differentiation capacities were assessed, followed by evaluation of hematopoietic support using cobblestone area-forming cell assay and long-term culture-initiating cell assay. RNA sequencing was performed to analyze the transcriptional profile of <i>p18</i><sup>−/−</sup> MSCs, with a focus on differentially expressed genes (DEGs). Key pathways associated with hematopoietic support were identified using Ingenuity Pathway Analysis. A candidate protein was quantified by ELISA, and its functional role in hematopoietic support was validated via a modified coculture system.</p> Results <p><i>p18</i><sup>−/−</sup> MSCs displayed an increased proliferation rate, preferential differentiation toward osteogenesis over adipogenesis, and enhanced hematopoietic support. RNA sequencing analysis identified 137 DEGs, with secreted phosphoprotein 1 (<i>Spp1</i>, encoding osteopontin, Opn) being significantly upregulated in <i>p18</i><sup>−/−</sup> MSCs. Elevated Opn levels were confirmed in both bone marrow and MSC-conditioned media from <i>p18</i><sup>−/−</sup> mice. Functional validation further demonstrated that Opn enhanced the hematopoietic supportive capacity of MSCs in vitro.</p> Conclusions <p><i>p18</i> deficiency promotes osteogenic differentiation and enhances the hematopoietic supportive function of MSCs, likely mediated by Opn upregulation. These findings suggest a potential therapeutic strategy for improving bone regeneration and HSC expansion.</p>

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Deletion of p18INK4c enhances both osteogenesis and hematopoietic supportive capacity of bone marrow mesenchymal stromal cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月1日

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  • Wen Xing,
  • Fang Dong,
  • Yining Liu,
  • Jiajia Yuan,
  • Chao Chen,
  • Yihan Li,
  • Han Wang,
  • Ming Yao,
  • Ting Chen,
  • Tao Cheng,
  • Sha Hao,
  • Yuan Zhou

摘要

Background

p18INK4 C (CDKN2C, encoded by p18INK4c or Cdkn2c) is an early G1-phase cyclin-dependent kinase inhibitor protein. Previous studies demonstrated enhanced self-renewal capacity of hematopoietic stem cells (HSCs) in p18−/− mice compared to wild-type (WT) mice. Given the critical role of bone marrow niche cells-particularly mesenchymal stromal cells (MSCs)-in hematopoiesis, this study investigated the functional alterations of p18−/− MSCs and their impact on hematopoietic support.

Methods

Bone marrow derived MSCs were isolated from p18−/− and WT mice. Their proliferation and differentiation capacities were assessed, followed by evaluation of hematopoietic support using cobblestone area-forming cell assay and long-term culture-initiating cell assay. RNA sequencing was performed to analyze the transcriptional profile of p18−/− MSCs, with a focus on differentially expressed genes (DEGs). Key pathways associated with hematopoietic support were identified using Ingenuity Pathway Analysis. A candidate protein was quantified by ELISA, and its functional role in hematopoietic support was validated via a modified coculture system.

Results

p18−/− MSCs displayed an increased proliferation rate, preferential differentiation toward osteogenesis over adipogenesis, and enhanced hematopoietic support. RNA sequencing analysis identified 137 DEGs, with secreted phosphoprotein 1 (Spp1, encoding osteopontin, Opn) being significantly upregulated in p18−/− MSCs. Elevated Opn levels were confirmed in both bone marrow and MSC-conditioned media from p18−/− mice. Functional validation further demonstrated that Opn enhanced the hematopoietic supportive capacity of MSCs in vitro.

Conclusions

p18 deficiency promotes osteogenic differentiation and enhances the hematopoietic supportive function of MSCs, likely mediated by Opn upregulation. These findings suggest a potential therapeutic strategy for improving bone regeneration and HSC expansion.