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The hematopoietic stem cells or HSCs are multipotent, meaning they can differentiate and give rise to all blood and immune cells. HSCs are maintained in the quiescent stage until an external stimulus initiates their differentiation. The multipotent HSCs exist as two heterogeneous populations, long-term repopulating cells (LTRC) and short-term repopulating cells (STRC). The two HSC populations have different surface markers or receptors and are classified based on quiescence and long-term...
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The stem cell niche is the dynamic microenvironment where stem cells reside. Inside these niches, the cells may remain undifferentiated, undergo high self-renewal, or become lineage-specific progenitors. Stem cells coexist with other niche cells, such as stromal cells. They also interact closely with the ECM. Cell-cell and cell-matrix communication occur via adhesion molecules or soluble factors that signal the stem cells and determine their fate. Stromal cells also provide survival signals to...
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Related Experiment Video

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An epitranscriptomic program maintains skeletal stem cell quiescence via a METTL3-FEM1B-GLI1 axis.

Jing Wang1,2, Weidong Liu1, Tiantian Zhang3

  • 1State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China.

The EMBO Journal
|February 27, 2025
PubMed
Summary

RNA m6A modifications are crucial for skeletal stem cell (SSC) function. Deleting Mettl3 impairs bone development by affecting SSC self-renewal and differentiation via the Hedgehog pathway.

Keywords:
FEM1BProteostasisQuiescenceRNA m6ASkeletal Stem Cell

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Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Stem Cell Biology

Background:

  • Skeletal stem cells (SSCs) are vital for skeletal maintenance through pluripotency and differentiation.
  • Precise regulation of SSC function for skeletal organization is not fully understood.

Purpose of the Study:

  • To investigate the role of RNA N6-adenosine (m6A) modification in skeletal cell populations.
  • To elucidate the mechanisms by which m6A regulates SSC identity and function.

Main Methods:

  • Analysis of the RNA m6A modification landscape in mouse epiphyseal skeletal cells.
  • Genetic deletion of Mettl3 in murine skeletal stem and progenitor cells.
  • Assessment of bone development, growth plate zonation, and bone mass.
  • Investigation of SSC quiescence, self-renewal, and differentiation capacity.
  • Mechanistic studies involving Fem1b mRNA stability and Gli1 protein levels.

Main Results:

  • m6A modifications are prevalent in SSCs and progenitors, influencing cell fate.
  • Mettl3 deletion in SSCs leads to impaired bone development, shortened limbs, disrupted growth plates, and reduced bone mass.
  • Mettl3 deficiency causes SSCs to exit quiescence, compromising self-renewal and differentiation.
  • Mettl3 regulates Fem1b mRNA stability, impacting Gli1 protein levels and Hedgehog pathway signaling.

Conclusions:

  • RNA m6A modification is essential for maintaining skeletal stem cell quiescence and potency.
  • Epitranscriptomic regulation of proteostasis plays a critical role in skeletal development and homeostasis.
  • The Mettl3-Fem1b-Gli1 axis is a key pathway for SSC identity and function.