# Thrombospondin 1 and 2 regulate mesenchymal progenitor cell fate and matrix organization

## TL;DR

This study shows that Thrombospondin 1 and 2 influence mesenchymal progenitor cell behavior and matrix organization during musculoskeletal injury repair and heterotopic ossification.

## Contribution

The study identifies TSP1 and TSP2 as key regulators of MPC/ECM interactions and HO progression.

## Key findings

- TSP1 is upregulated in macrophages and MPCs at injury sites, while TSP2 is found in MPCs around HO anlagen.
- TSP1/2 double knockout mice show reduced HO volume and disrupted ECM alignment.
- TSP1 and TSP2 are critical for HO formation and could be therapeutic targets.

## Abstract

Thrombospondin 1 and 2 (TSP1 and TSP2) are critical regulators of extracellular matrix (ECM) interactions, influencing cell differentiation and tissue repair. Recent discoveries from our laboratory and others highlight the importance of altered ECM alignment in influencing aberrant mesenchymal progenitor cell (MPC) differentiation and subsequent ectopic bone formation in trauma-induced heterotopic ossification (HO). However, the key regulators of this MPC to ECM interaction have yet to be elucidated. This study uncovers the role of matricellular TSP1 and TSP2 in MPC/ECM interaction as well as HO formation and progression. Using single-cell RNA sequencing, spatial transcriptomics, and in vivo models, we found that TSP1 is upregulated in tissue remodeling macrophages and MPCs at the injury site, while TSP2 is restricted to MPCs surrounding the HO anlagen. TSP1/2 double knockout (DKO) mice exhibited significantly reduced HO volume and disrupted ECM alignment. These findings highlight the crucial roles of TSP1 and TSP2 in musculoskeletal injury repair as well as HO formation and progression, supporting the potential to therapeutically target TSP1 and TSP2 to prevent HO.