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

作者：Jessica E. Ackerman, Katherine T. Best, Samantha Muscat, Elizabeth M. Pritchett, Anne E. C. Nichols, Chia‐Lung Wu, Alayna E. Loiselle · 发表于：Cell Reports · 年份：2022 · DOI：10.1016/j.celrep.2022.111706 · 被引用次数：55 · 研究领域：Tendon Structure and Treatment、Cellular Mechanics and Interactions、Viral Infectious Diseases and Gene Expression in Insects

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.