Immobilization after injury alters extracellular matrix and stem cell fate.

The Journal of Clinical Investigation
Amanda HuberBenjamin Levi

Abstract

Cells sense the extracellular environment and mechanical stimuli and translate these signals into intracellular responses through mechanotransduction, which alters cell maintenance, proliferation, and differentiation. Here we use a mouse model of trauma-induced heterotopic ossification (HO) to examine how cell-extrinsic forces impact mesenchymal progenitor cell (MPC) fate. After injury, single-cell (sc) RNA sequencing of the injury site reveals an early increase in MPC genes associated with pathways of cell adhesion and ECM-receptor interactions, and MPC trajectories to cartilage and bone. Immunostaining uncovers active mechanotransduction after injury with increased focal adhesion kinase signaling and nuclear translocation of transcriptional coactivator TAZ, inhibition of which mitigates HO. Similarly, joint immobilization decreases mechanotransductive signaling, and completely inhibits HO. Joint immobilization decreases collagen alignment and increases adipogenesis. Further, scRNA sequencing of the HO site after injury with or without immobilization identifies gene signatures in mobile MPCs correlating with osteogenesis, and signatures from immobile MPCs with adipogenesis. scATAC-seq in these same MPCs confirm that in mobile ...Continue Reading

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Citations

Sep 10, 2020·Nature Reviews. Molecular Cell Biology·Ankit SalhotraMichael T Longaker
Mar 16, 2021·Stem Cells and Development·Nicole J EdwardsBenjamin Levi
Jun 25, 2021·Science Translational Medicine·Qian CongYingzi Yang
Oct 13, 2021·The Journal of Bone and Joint Surgery. American Volume·Philipp Leucht, Thomas A Einhorn

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Methods Mentioned

BETA
single-cell sequencing
nuclear translocation
atomic force microscopy
AFM
scRNA sequencing

Software Mentioned

Monocle
ImageJ
FibrilTool
AtomicJ
scATAC

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