Spinal cord injury reprograms muscle ﬁbroadipogenic progenitors to form heterotopic bones within muscles

Bone Research, 2022 · DOI: https://doi.org/10.1038/s41413-022-00188-y · Published: October 11, 2022

Spinal Cord Injury Regenerative Medicine Musculoskeletal Medicine

Simple Explanation

Neurogenic heterotopic ossifications (NHOs) are pathological heterotopic bones that develop in peri-articular muscles following severe lesions of the central nervous system, such as spinal cord injuries (SCIs). NHOs are frequent, with an incidence of 10%–23% in patients with traumatic brain injury and 10%–53% in patients with SCIs, increasing to 68% in victims of severe combat blast injuries involving the spine. Adult skeletal muscles contain two populations of stem/progenitor cells: (1) satellite cells (SCs), residing within the myoﬁber under the myoﬁber basal lamina, which regenerate myoblasts and myocytes following injury and are as such true muscle stem cells, and (2) ﬁbroadipogenic progenitors (FAPs) residing in the interstitial space between myoﬁbers. Following muscle injury, SCI causes the upregulation of PDGFRα expression on FAPs but not SCs and the failure of SCs to regenerate myoﬁbers in the injured muscle, with reduced apoptosis and continued proliferation of muscle resident FAPs enabling their osteogenic differentiation into NHOs.

Study Duration

Not specified

Participants

Mice and human NHO biopsies

Evidence Level

Not specified

Key Findings

1
NHOs developing after SCI in injured muscles in mice are not derived from muscle SCs. We also reveal that NHOs only develop in areas of the injured muscle where SCs fail to regenerate myoﬁbers.
2
We found focal accumulation and osteoblastic differentiation of the Prrx1-expressing PDGFRα+ mesenchymal progenitor cells among areas of NHO development in the Prrx1ZsG mice.
3
SCI causes the selective upregulation of PDGFRα expression at the surface of muscle FAPs independent of the muscle injury itself, with no such effect on SCs.

Research Summary

This study investigates the cellular origin of neurogenic heterotopic ossifications (NHOs), which frequently develop in muscles after spinal cord injuries (SCIs). Using lineage-tracing experiments in mice, the study demonstrates that NHOs are derived from fibroadipogenic progenitors (FAPs), not satellite cells (SCs). The research shows that SCI causes upregulation of PDGFRα expression on FAPs, impairs SC-mediated muscle regeneration, and leads to reduced apoptosis and increased proliferation of FAPs. These reprogrammed FAPs then differentiate into osteoblasts, forming NHOs. Validation with human NHO biopsies revealed that PDGFRα+ mesenchymal cells isolated from muscle surrounding NHOs could develop ectopic bones when transplanted into immunocompromised mice, further supporting the role of FAPs in NHO formation.

Practical Implications

Therapeutic Targets

Identifying FAPs as the source of NHOs opens possibilities for targeted therapies to prevent or treat NHO development after SCI.

Understanding SCI Pathophysiology

The study highlights the role of SCI in reprogramming FAPs, providing insights into the complex interplay between the nervous system and musculoskeletal system after injury.

Clinical Relevance

The findings suggest that interventions aimed at modulating FAP activity, such as targeting PDGFRα signaling or promoting FAP apoptosis, could reduce NHO formation and improve outcomes for SCI patients.

Study Limitations

1
Parabiosis experiments are forbidden for ethical reasons in Australia.
2
Lineage tracing experiments are not possible in humans.
3
Because of the small amount of muscle tissue on the surgical residues, adherent cells were ampliﬁed before and after sorting, possibly resulting in slight phenotypic changes.

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