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

Stem Cell Reports. 2021 Mar 9;16(3):626-640. doi: 10.1016/j.stemcr.2021.01.011. Epub 2021 Feb 18.


Heterotopic ossification (HO) is a form of pathological cell-fate change of mesenchymal stem/precursor cells (MSCs) that occurs following traumatic injury, limiting range of motion in extremities and causing pain. MSCs have been shown to differentiate to form bone; however, their lineage and aberrant processes after trauma are not well understood. Utilizing a well-established mouse HO model and inducible lineage-tracing mouse (Hoxa11-CreERT2;ROSA26-LSL-TdTomato), we found that Hoxa11-lineage cells represent HO progenitors specifically in the zeugopod. Bioinformatic single-cell transcriptomic and epigenomic analyses showed Hoxa11-lineage cells are regionally restricted mesenchymal cells that, after injury, gain the potential to undergo differentiation toward chondrocytes, osteoblasts, and adipocytes. This study identifies Hoxa11-lineage cells as zeugopod-specific ectopic bone progenitors and elucidates the fate specification and multipotency that mesenchymal cells acquire after injury. Furthermore, this highlights homeobox patterning genes as useful tools to trace region-specific progenitors and enable location-specific gene deletion.

Keywords: Hoxa11; aberrant differentiation; heterotopic ossification; mesenchymal progenitors; tendon.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism
  • Animals
  • Bone and Bones / metabolism*
  • Cell Differentiation*
  • Cell Lineage*
  • Chondrocytes / metabolism
  • Disease Models, Animal
  • Ectopic Gene Expression
  • Epigenomics
  • Female
  • Gene Expression Profiling
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Male
  • Mesenchymal Stem Cells / metabolism*
  • Mice
  • Mice, Transgenic
  • Muscle, Skeletal / metabolism
  • Ossification, Heterotopic / genetics*
  • Ossification, Heterotopic / metabolism*
  • Ossification, Heterotopic / pathology
  • Osteoblasts / metabolism
  • Osteogenesis*
  • Single-Cell Analysis
  • Tendons / metabolism


  • Homeodomain Proteins
  • Hoxa11 protein, mouse