Healing without scarring

doi:10.1126/science.abi5770

GSTDTAP > 气候变化

DOI	10.1126/science.abi5770
	Healing without scarring
	Piotr Konieczny; Shruti Naik
	2021-04-23
发表期刊	Science
出版年	2021
英文摘要	Rapid repair and restoration of tissue integrity after injury is vital for organismal survival. Some lower vertebrates and invertebrates possess the extraordinary ability to regenerate functional tissues throughout their lifetime ([ 1 ][1]). In mammals, however, tissue regeneration is largely restricted to gestation. In the terrestrial environment, evolutionary pressures to heal have favored the rapid formation of fibrotic tissue (or scar tissue) instead of recreating original tissue architecture ([ 2 ][2]). Scarring-related tissue dysfunction remains a major health care challenge with limited treatment options. Thus, scar prevention and regeneration of functional tissues is a coveted goal of tissue repair. On page 362 of this issue, Mascharak et al. ([ 3 ][3]) point to a therapeutic target for tissue regeneration by revealing how specific fibroblasts produce scars in response to skin wounding. A subset of mammalian dermal fibroblasts that express the transcription factor Engrailed-1 (En-1) was previously identified as responsible for scar deposition, raising the tantalizing possibility that modulating this lineage of En-1–positive fibroblasts (EPFs) may limit scarring ([ 4 ][4]). Mascharak et al. now report the presence of subsets of “profibrotic” EPFs and “proregenerative” fibroblasts that do not express En-1 [En-1–negative fibroblasts (ENFs)] in adult murine skin wounds. They further identified mechanotransduction—that is, sensing and converting mechanical stimuli into biochemical signals—through the transcription factor Yes-associated protein (YAP) as a key signal involved in the conversion of wound ENFs to EPFs. Genetic and pharmacological inhibition of YAP was sufficient to block EPF and scarring in mice. Notably, abrogating the EPF scar response led to ENF-mediated restoration of skin appendages, tensile strength, and extracellular matrix architecture that matches that of unwounded skin (see the figure). The discovery of diverse fibroblast populations across different organ systems and between anatomical sites within the same organ has underscored highly specialized roles for these cells in health and disease. For instance, functionally distinct populations of fibroblasts reside in different layers of the dermis and contribute to skin development and wound responses ([ 5 ][5]). Although embryonic and wounded skin are replete with scar-forming EPFs, healthy postnatal skin conspicuously lacks these cells. Then, an open question is where scar-forming postnatal wound EPFs come from. Are they generated by a resurgence of embryonic EPFs or by the direct conversion of adult ENFs to EPFs in the wound bed? To address this, Mascharak et al. fractionated ENFs from the mouse upper or papillary dermis, middle or reticular dermis, and lower or hypodermis and transplanted these populations into a secondary wound environment in genetically matched host animals. Consistent with previous studies highlighting the importance of a specific subset of reticular fibroblasts in fibrosis ([ 5 ][5]), the authors observed that ENFs from the reticular dermis preferentially up-regulated En1 expression and converted to EPFs after transplantation. By contrast, papillary dermal ENFs failed to generate EPFs, and ENFs demonstrated a propensity toward the adipocyte lineage. How this potential is imposed on reticular ENFs by developmental and/or microenvironmental cues awaits investigation. Fibroblasts are particularly sensitive to mechanical cues, and increased wound tension triggers profibrotic responses ([ 5 ][5]). Mascharak et al. examined if and how mechanical forces promote En-1 expression in ENFs by culturing ENFs on plastics of varying stiffness. Reticular ENFs converted to EPFs on high-stiffness plastic but failed to do so on soft hydrogel. This ENF-to-EPF transition was blocked by inhibiting Rho kinase, a canonical mediator of mechanotransduction. When mouse skin was artificially stretched, both unwounded and wounded skin had increased expression of fibroblast YAP and alpha smooth muscle actin (α-SMA), two key indicators of the fibrotic response ([ 6 ][6]). Moreover, YAP, a mechanosensitive transcription factor, showed increased nuclear localization in ENFs but not EPFs. Pharmacological inhibition of YAP in mechanically loaded wounds limited the generation of EPFs, suggesting that YAP controls the switch to a “profibrotic” EPF fate. A transcriptomics time course of reticular ENFs revealed an enrichment of integrin signaling and collagen-related pathways, which were reversed by YAP inhibition. Whether En-1 is a direct transcriptional target of YAP or is circuitously activated by other factors is yet to be determined. Additionally, En-1 is a homeobox transcription factor with a central role in midbrain development ([ 7 ][7]). Untangling the complex gene regulatory circuits involving YAP and En-1 that specify EPF fate and function warrants further study. ![Figure][8] Specific fibroblasts orchestrate tissue regeneration in adult mammalian skin Classic wound healing has favored the rapid formation of fibrotic tissue or scar tissue. Blocking mechanotransduction by YAP inhibition prevents the transition of proregenerative fibroblasts (ENFs) to proscarring fibroblasts (EPFs) and simultaneously promotes tissue regeneration, hair follicle neogenesis, tensile strength, and extracellular matrix (ECM) organization. GRAPHIC: KELLIE HOLOSKI/ SCIENCE To formally confirm that EPFs were responsible for scar formation, Mascharak et al. genetically ablated these cells from wounds. The absence of EPFs not only limited scar formation but also unexpectedly resulted in the regeneration of hair follicles and appendages. Both chemical inhibition and genetic deletion of YAP in fibroblasts also limited scarring and recapitulated the regenerative phenotype observed after genetic ablation of EPFs. Notably, an unbiased machine-learning analysis of tissue ultrastructure revealed that the organization of the extracellular matrix after YAP inhibition more closely resembled that of unwounded skin. Previous attempts to modulate tension reduced scarring but failed to regenerate tissue ([ 8 ][9]). Thus, simply reducing collagen (a constituent of the extracellular matrix) deposition by fibroblasts may not be sufficient to promote regeneration, which likely requires complex remodeling of tissue architecture and other secondary cues driven by loss of YAP. YAP mechanosignaling underlies the pathology of liver cirrhosis and idiopathic pulmonary fibrosis that compromise organ function ([ 6 ][6], [ 9 ][10]). Similarly targeting profibrotic fibroblast populations could be a therapeutic strategy to limit scarring and restore tissue function in a range of fibrotic diseases. In the study of Mascharak et al. , ENF-mediated skin regeneration (as the result of YAP inhibition) is defined by three key criteria: regeneration of epidermal appendages (hair follicles and glands), reestablishment of extracellular matrix architecture identical to that in healthy skin, and restoration of tensile strength to healthy skin levels. Perhaps regeneration is a default state that is outpaced by scarring in mammalian repair. If so, what are the molecular mediators of regeneration, and do distinct cues govern each facet of regeneration, for example, hair follicle neogenesis versus tensile strength? Previous studies have attributed the sparse de novo regeneration of hair follicles in large wounds to the resurgence of developmental signals ([ 10 ][11]). Whether similar mechanisms are at play or whether modulating mechanotransduction engages distinct pathways that are tailored to adult regeneration begets further investigation. Tissue scarring is a leading cause of morbidity and mortality worldwide ([ 11 ][12]). The findings by Mascharak et al. thus hold great promise not only for antifibrotic therapies but also for the simultaneous activation of the skin's regenerative properties. 1. [↵][13]1. G. C. Gurtner, 2. S. Werner, 3. Y. Barrandon, 4. M. T. Longaker , Nature 453, 314 (2008). 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领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/324069
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Piotr Konieczny,Shruti Naik. Healing without scarring[J]. Science,2021.
APA	Piotr Konieczny,&Shruti Naik.(2021).Healing without scarring.Science.
MLA	Piotr Konieczny,et al."Healing without scarring".Science (2021).