Defining the spatial-molecular map of fibrotic tendon healing and the drivers of Scleraxis-lineage cell fate and function

• Published in: Cell reports (Cambridge) Vol. 41; no. 8; p. 111706
• Main Authors: Ackerman, Jessica E, Best, Katherine T, Muscat, Samantha N, Pritchett, Elizabeth M, Nichols, Anne E C, Wu, Chia-Lung, Loiselle, Alayna E
• Format: Journal Article
• Language: English
• Published: United States 22-11-2022
• Subjects: Animals; Cell Differentiation; Cicatrix; Fibroblasts; Mice; Tendons; Wound Healing; Scleraxis; tendon; fibrosis; CP: Cell biology; myofibroblast; spatial transcriptomics
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.111706

Tendon injuries heal via a scar-mediated response, and there are no biological approaches to promote more regenerative healing. Mouse flexor tendons heal through the formation of spatially distinct tissue areas: a highly aligned tissue bridge between the native tendon stubs that is enriched for adult Scleraxis-lineage cells and a disorganized outer shell associated with peri-tendinous scar formation. However, the specific molecular programs that underpin these spatially distinct tissue profiles are poorly defined. In the present study, we combine lineage tracing of adult Scleraxis-lineage cells with spatial transcriptomic profiling to define the overarching molecular programs that govern tendon healing and cell-fate decisions. Pseudotime analysis identified three fibroblast trajectories (synthetic, fibrotic, and reactive) and key transcription factors regulating these fate-switching decisions, including the progression of adult Scleraxis-lineage cells through the reactive trajectory. Collectively, this resource defines the molecular mechanisms that coordinate the temporo-spatial healing phenotype, which can be leveraged to inform therapeutic candidate selection.