Conventional thinking is that bone regeneration is left to a small number of mighty cells called skeletal stem cells, which reside within larger groups of bone marrow stromal cells.
But new findings recasts that thinking. In a recent study, researchers report that mature bone marrow stromal cells metamorphosed to perform in ways similar to their bone-healing stem cell cousins--but only after an injury.
Bone fracture is an emergency for humans and all vertebrates, so the sooner cells start the business of healing damaged bone--and the more cells there are to do it--the better.
"Our study shows that other cells besides skeletal stem cells can do this job as well," the senior author said.
In the mouse study, inert Cxcl12 cells in bone marrow responded to post-injury cellular cues by converting into regenerative cells, much like skeletal stem cells. Normally, the main job of these Cxcl12-expressing cells, widely known as CAR cells, is to secrete cytokines, which help regulate neighboring blood cells. They were recruited for healing only after an injury.
A combined single cell RNA-seq analysis demonstrate that these cells convert their identity into a skeletal stem cell-like state in response to injury, associated with upregulation of osteoblast-signature genes and activation of canonical Wnt signaling components along the single-cell trajectory.
β-catenin deficiency in these cells indeed causes insufficiency in cortical bone regeneration. Therefore, quiescent Cxcl12-creER+ BMSCs transform into osteoblast precursor cells in a manner mediated by canonical Wnt signaling, highlighting a unique mechanism by which dormant stromal cells are enlisted for skeletal regeneration.
"The surprise in our study is that these cells essentially did nothing in terms of making bones, when bones grow longer," the author said. "It's only when bones are injured that these cells start rushing to repair the defect."
This is important because the remarkable regenerative potential of bones is generally attributed to rare skeletal stem cells, the author says. These new findings raise the possibility that these mighty skeletal stem cells could be generated through the transformation of the more available mature stromal cells.
These mature stromal cells are malleable and readily available throughout life, and could potentially provide an excellent cellular source for bone and tissue regeneration, the author says.
Bone regeneration after injury does not involve stem cells!
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