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Novel Lineage-Tracing System to Identify Site-Specific Ectopic Bone Precursor Cells.

Chase A Pagani1, Amanda K Huber2, Charles Hwang2

  • 1Center for Organogenesis and Trauma, Department of Surgery, University of Texas Southwestern, 6000 Harry Hines Boulevard, Dallas, TX 75235, USA.

Stem Cell Reports
|February 19, 2021
PubMed
Summary

This study identifies Hoxa11-lineage cells as specific progenitors of ectopic bone formation in the zeugopod after injury. These mesenchymal stem/precursor cells gain multipotency, differentiating into bone, cartilage, and fat cells.

Keywords:
Hoxa11aberrant differentiationheterotopic ossificationmesenchymal progenitorstendon

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Area of Science:

  • Regenerative Medicine
  • Developmental Biology
  • Skeletal Biology

Background:

  • Heterotopic ossification (HO) involves pathological cell-fate changes in mesenchymal stem/precursor cells (MSCs) after injury, causing pain and limited mobility.
  • The precise lineage and post-traumatic behavior of MSCs contributing to HO remain unclear.

Purpose of the Study:

  • To identify specific progenitor cells responsible for heterotopic ossification in the zeugopod.
  • To elucidate the molecular mechanisms and cell-fate plasticity of mesenchymal cells following traumatic injury.

Main Methods:

  • Utilized a mouse model of heterotopic ossification combined with inducible lineage tracing (Hoxa11-CreERT2;ROSA26-LSL-TdTomato).
  • Performed bioinformatic analyses, including single-cell transcriptomics and epigenomics, on Hoxa11-lineage cells.

Main Results:

  • Identified Hoxa11-lineage cells as specific progenitors of HO within the zeugopod.
  • Demonstrated that these cells are regionally restricted mesenchymal cells that acquire differentiation potential towards chondrocytes, osteoblasts, and adipocytes post-injury.
  • Revealed the fate specification and multipotency acquired by mesenchymal cells after injury.

Conclusions:

  • Hoxa11-lineage cells are zeugopod-specific progenitors of ectopic bone.
  • Mesenchymal cells gain multipotency and specific differentiation pathways after traumatic injury.
  • Homeobox patterning genes are valuable tools for tracing region-specific progenitors and enabling targeted gene deletion.