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Fibrosis is a common manifestation of most progressive and degenerative diseases, with myofibroblast activation and matrix accumulation playing a key role. In this issue of the JCI, Hoeft et al. identify the important role of ADAMTS12 in fibroblast activation. ADAMTS12, a secreted protein, is involved in extracellular matrix (ECM) remodeling, cell signaling, and inflammation. ADAMTS12 facilitates proteolysis by cleaving various substrates such as ECM components, which are vital for cellular signaling and remodeling. Additionally, it modulates cell-matrix interactions, influencing cell adhesion and migration, and plays an important role in the inflammatory processes. Understanding the role of ADAMTS12 offers potential therapeutic insights for targeting fibrosis in progressive diseases., Fibrosis in heart and kidney disease Fibrosis is a pathological process characterized by excessive accumulation of extracellular matrix (ECM) components, particularly collagen, in organs, including the heart and kidneys, often [...]

Fibrosis represents the uncontrolled replacement of parenchymal tissue with extracellular matrix (ECM) produced by myofibroblasts. While genetic fate-tracing and single-cell RNA-Seq technologies have helped elucidate fibroblast heterogeneity and ontogeny beyond fibroblast to myofibroblast differentiation, newly identified fibroblast populations remain ill defined, with respect to both the molecular cues driving their differentiation and their subsequent role in fibrosis. Using an unbiased approach, we identified the metalloprotease ADAMTS12 as a fibroblast-specific gene that is strongly upregulated during active fibrogenesis in humans and mice. Functional in vivo KO studies in mice confirmed that Adamts12 was critical during fibrogenesis in both heart and kidney. Mechanistically, using a combination of spatial transcriptomics and expression of catalytically active or inactive ADAMTS12, we demonstrated that the active protease of ADAMTS12 shaped ECM composition and cleaved hemicentin 1 (HMCN1) to enable the activation and migration of a distinct injury- responsive fibroblast subset defined by aberrant high JAK/STAT signaling., Introduction Fibrosis represents the uncontrolled replacement of parenchymal tissue by extracellular matrix (ECM) (1). Whereas deposition of ECM sustains tissue integrity immediately after injury, continued deposition of ECM by myofibroblasts [...]

Hypertrophic scar (HS) results from abnormal wound healing, accompanied by excessive hypercellularity, migration, and extracellular matrix (ECM) deposition. Autophagy dysregulation plays crucial roles during HS formation. The over-expressed p75 neurotrophin receptor (p75NTR) in injured skin tissue after wound healing becomes a factor aggravating scar. This study was designed to investigate the role of p75NTR and p75NTR-mediated autophagy in the process of HS. The results revealed that p75NTR expression was significantly upregulated while that of autophagy proteins was down-regulated in cicatrix at 3 and 6 months after a burn, which was recovered at 12 months. p75NTR silencing inhibited proliferation, migration, and ECM deposition of hypertrophic scar fibroblasts (HSF), whereas p75NTR overexpression presented the opposite results. Silencing of p75NTR reduced the expression of PI3K/Akt/mTOR signaling molecules while enhancing that of autophagy proteins. Importantly, PI3K agonist (IGF-1) intervention notably decreased the levels of LC3B II/I and Beclin-1 and restored the inhibitory effects of p75NTR silencing on proliferation, migration, and ECM deposition of HSF. Concurrently, autophagy inhibitor 3-methyladenine (3-MA) treatment exhibited the same variation trends with IGF-1. Taken together, these findings demonstrated that p75NTR silencing inhibits proliferation, migration, and ECM deposition of HSF by activating autophagy by inhibiting the PI3K/Akt/mTOR pathway. Key words: autophagy, proliferation, migration, extracellular matrix deposition, hypertrophic scar fibroblasts. La cicatrisation hypertrophique (CH) provient d'une guerison de plaie anormale accompagnee d'une hypercellularite, de migration, ainsi que du depot de matrice extracellulaire (MEC) excessifs. Le dereglement de l'autophagie joue des roles cruciaux dans l'avenement de la CH. La surexpression des recepteurs de la neurotrophine p75 (p75NTR) dans le tissu cutane lese apres la guerison de plaie devient un facteur aggravant de la cicatrisation. Ces travaux ont ete concus en vue d'etudier le role des p75NTR et de l'autophagie mediee par les p75NTR au cours du processus de CH. Les resultats ont revele que l'expression des p75NTR etait nettement regulee a la hausse, tandis que les proteines de l'autophagie etaient regulees a la baisse dans la cicatrice 3 et 6 mois apres une brulure, laquelle s'etait retablie a 12 mois. La repression des p75NTR permettait d'attenuer la proliferation et la migration des fibroblastes de la cicatrisation hypertrophique (FCH), ainsi que le depot de MEC qu'ils produisent, alors que la surexpression des p75NTR donnait des resultats opposes. La repression des p75NTR entrainait une diminution de l'expression des molecules de la voie de signalisation PI3K/Akt/mTOR, avec une hausse des proteines de l'autophagie. Il est important de noter que la participation d'un agoniste de la PI3K (l'IGF-1) entrainait une diminution notable des taux de LC3B II/I et de becline-1, avec un retablissement des effets inhibiteurs de la repression des p75NTR sur la proliferation et la migration des FCH, ainsi que du depot de MEC qu'ils produisent. Simultanement, l'administration de 3-methyladenine (3-MA), un inhibiteur de l'autophagie, entrainait les memes tendances aux variations avec l'IGF-1. Ces resultats reunis montraient que la repression des p75NTR entraine une inhibition de la proliferation et de la migration des FCH, ainsi que du depot de MEC qu'ils produisent en activant l'autophagie par l'intermediaire de l'inhibition de la voie de signalisation PI3K/Akt/mTOR. [Traduit par la Redaction] Mots-cles : autophagie, proliferation, migration, depot de matrice extracellulaire, fibroblastes de la cicatrisation hypertrophique., Introduction Hypertrophic scar (HS), widely considered as a type of complication of skin injury, is frequently observed after wound healing of human skin caused by burns, lacerations, and surgery (Miletta [...]

The pancreas originates from two epithelial evaginations of the foregut, which consist of multipotent epithelial progenitors that organize into a complex tubular epithelial network. The trunk domain of each epithelial branch consists of bipotent pancreatic progenitors (bi-PPs) that give rise to both duct and endocrine lineages, whereas the tips give rise to acinar cells.sup.1. Here we identify the extrinsic and intrinsic signalling mechanisms that coordinate the fate-determining transcriptional events underlying these lineage decisions.sup.1,2. Single-cell analysis of pancreatic bipotent pancreatic progenitors derived from human embryonic stem cells reveal that cell confinement is a prerequisite for endocrine specification, whereas spreading drives the progenitors towards a ductal fate. Mechanistic studies identify the interaction of extracellular matrix (ECM) with integrin [alpha]5 as the extracellular cue that cell-autonomously, via the F-actin-YAP1-Notch mechanosignalling axis, controls the fate of bipotent pancreatic progenitors. Whereas ECM-integrin [alpha]5 signalling promotes differentiation towards the duct lineage, endocrinogenesis is stimulated when this signalling cascade is disrupted. This cascade can be disrupted pharmacologically or genetically to convert bipotent pancreatic progenitors derived from human embryonic stem cells to hormone-producing islet cells. Our findings identify the cell-extrinsic and intrinsic mechanotransduction pathway that acts as gatekeeper in the fate decisions of bipotent pancreatic progenitors in the developing pancreas. Single-cell analysis reveals that interactions with the extracellular matrix via integrin [alpha]5 and mechanotransducer YAP1 determine whether pancreatic progenitors develop along the duct or endocrine lineages., Author(s): Anant Mamidi [sup.1] , Christy Prawiro [sup.1] , Philip A. Seymour [sup.1] , Kristian Honnens de Lichtenberg [sup.1] , Abigail Jackson [sup.1] , Palle Serup [sup.1] , Henrik Semb [...]

Author(s): Elwira Smakowska-Luzan [1]; G. Adam Mott [2]; Katarzyna Parys [1]; Martin Stegmann [3]; Timothy C Howton [4]; Mehdi Layeghifard [2]; Jana Neuhold [5]; Anita Lehner [5]; Jixiang Kong [1]; [...]

Fibroblasts are the major mesenchymal cell type in connective tissue and deposit the collagen and elastic fibres of the extracellular matrix (ECM) (1). Even within a single tissue, fibroblasts exhibit considerable functional diversity, but it is not known whether this reflects the existence of a differentiation hierarchy or is a response to different environmental factors. Here we show, using transplantation assays and lineage tracing in mice, that the fibroblasts of skin connective tissue arise from two distinct lineages. One forms the upper dermis, including the dermal papilla that regulates hair growth and the arrector pili muscle, which controls piloerection. The other forms the lower dermis, including the reticular fibroblasts that synthesize the bulk of the fibrillar ECM, and the preadipocytes and adipocytes of the hypodermis. The upper lineage is required for hair follicle formation. In wounded adult skin, the initial wave of dermal repair is mediated by the lower lineage and upper dermal fibroblasts are recruited only during re-epithelialization. Epidermal b-catenin activation stimulates the expansion of the upper dermal lineage, rendering wounds permissive for hair follicle formation. Our findings explain why wounding is linked to formation of ECMrich scar tissue that lacks hair follicles (2-4). They also form a platform for discovering fibroblast lineages in other tissues and for examining fibroblast changes in ageing and disease., At embryonic day (E)12.5 mouse epidermis comprises one or two cell layers and the dermis appears homogeneous in composition (Fig. 1a) (5). By E18.5 the epidermis is fully stratified, contains [...]