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Cdkn1a deletion or suppression by cyclic stretch enhance the osteogenic potential of bone marrow mesenchymal stem
Cassandra M Juran1, Justina Zvirblyte2, Margareth Cheng-Campbell3
1Blue Marble Space Institute of Science at NASA Ames Research Center, Mountain View, CA 94043, USA.
Abstract:
CDKN1A/P21 is a potent inhibitor of cell cycle progression and its overexpression is thought to be associated with inhibition of normal bone regenerative osteogenesis during spaceflight. To test whether CDKN1A/P21 regulates osteogenesis in response to mechanical loading we studied cyclic stretch versus static culture of Cdkn1a-/- (null) or wildtype primary mouse bone marrow osteoprogenitors during 21-day ex-vivo mineralization assays. Cyclically stretched Cdkn1a-/- cells are 3.95-fold more proliferative than wildtype, while static Cdkn1a-/- cells show a 2.50-fold increase. Furthermore, stage-specific single cell RNAseq analyses show expression of Cdkn1a is strongly suppressed by cyclic stretch in early and late osteoblasts, and minimally in the progenitor population. Lastly, both stretch and/or Cdkn1a deletion cause population shift from osteoprogenitors to osteoblasts, also indicating increased differentiation. Collectively, our results support the hypothesis that Cdkn1a constitutively plays a mechano-reversible anti-proliferative role during osteogenesis and suggests a new molecular target to counter regenerative deficits caused by disuse.
Insights
CDKN1A/P21 inhibits bone cell proliferation. Removing CDKN1A/P21 enhances osteogenesis under mechanical loading, suggesting it as a target for bone regeneration therapies.
Area of Science:
- Biomedical Engineering
- Cell Biology
- Orthopedics
Background:
- CDKN1A/P21 inhibits cell cycle progression.
- Overexpression of CDKN1A/P21 may impede bone regeneration during spaceflight.
- Mechanical loading influences bone cell differentiation and proliferation.
Purpose of the Study:
- To investigate the role of CDKN1A/P21 in regulating osteogenesis in response to mechanical loading.
- To determine if CDKN1A/P21 deletion affects osteoprogenitor proliferation and differentiation.
Main Methods:
- Primary mouse bone marrow osteoprogenitors (wildtype and Cdkn1a-/-) were cultured under cyclic stretch or static conditions for 21 days.
- Ex-vivo mineralization assays were performed.
- Stage-specific single-cell RNA sequencing was utilized to analyze gene expression.
Main Results:
- Cyclically stretched Cdkn1a-/- cells showed significantly higher proliferation (3.95-fold) compared to wildtype.
- Static Cdkn1a-/- cells also exhibited increased proliferation (2.50-fold).
- CDKN1A/P21 expression was suppressed by cyclic stretch in osteoblasts, and its deletion promoted osteoblast differentiation.
Conclusions:
- CDKN1A/P21 acts as a mechano-reversible, anti-proliferative factor during osteogenesis.
- Targeting CDKN1A/P21 may offer a strategy to counteract bone regenerative deficits caused by disuse or spaceflight.
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