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Model of the role of myofibroblasts during the healing of an open wound.a | In normal tissues, fibroblasts experience a relatively low amount of tension owing to stress-shielding by the surrounding collagen matrix, such that the organization of a contractile cytoskeleton is not stimulated (light pink area of dermis). When a full-thickness dermal wound is filled by a fibrin clot, local growth factors stimulate fibroblasts from the adjacent intact dermis to invade this provisional matrix. These migrating fibroblasts, along with vessels, fill the wound, which results in the formation of granulation tissue. At this point, fibroblasts are already stimulated to produce ED-A fibronectin (ED-A FN). b | Migrating fibroblasts exert tractional forces on the collagen matrix, which results in its reorganization along lines of stress. The development of mechanical stress stimulates fibroblasts to develop stress fibres and to produce collagen, so they acquire the proto-myofibroblast phenotype. Tensional forces and growth factors stimulate proto-myofibroblasts to secrete transforming growth factor 1 (TGF-1) and increased levels of ED-A FN. c | In a feedback loop, proto-myofibroblasts become differentiated myofibroblasts by synthesizing -smooth muscle actin and generating increased contractile force. At the same time, differentiated myofibroblasts lay down collagen and other extracellular-matrix (ECM) components, and produce proteases. This complex process of remodelling results in shortening of the collagen matrix with corresponding wound closure. d | When a normal healing wound closes, myofibroblasts disappear by apoptosis and a scar is formed. e | However, in many pathological situations, such as hypertrophic scar formation, myofibroblasts persist and continue to remodel the ECM, which results in connective-tissue contracture. In conclusion, myofibroblasts, far from being a 'bad' cell type, are functionally essential cells. It is their dysregulation that is the cause of tissue dysfunction.

Model of the role of myofibroblasts during the healing of an open wound.a | In normal tissues, fibroblasts experience a relatively low amount of tension owing to stress-shielding by the surrounding collagen matrix, such that the organization of a contractile cytoskeleton is not stimulated (light pink area of dermis). When a full-thickness dermal wound is filled by a fibrin clot, local growth factors stimulate fibroblasts from the adjacent intact dermis to invade this provisional matrix. These migrating fibroblasts, along with vessels, fill the wound, which results in the formation of granulation tissue. At this point, fibroblasts are already stimulated to produce ED-A fibronectin (ED-A FN). b | Migrating fibroblasts exert tractional forces on the collagen matrix, which results in its reorganization along lines of stress. The development of mechanical stress stimulates fibroblasts to develop stress fibres and to produce collagen, so they acquire the proto-myofibroblast phenotype. Tensional forces and growth factors stimulate proto-myofibroblasts to secrete transforming growth factor 1 (TGF-1) and increased levels of ED-A FN. c | In a feedback loop, proto-myofibroblasts become differentiated myofibroblasts by synthesizing -smooth muscle actin and generating increased contractile force. At the same time, differentiated myofibroblasts lay down collagen and other extracellular-matrix (ECM) components, and produce proteases. This complex process of remodelling results in shortening of the collagen matrix with corresponding wound closure. d | When a normal healing wound closes, myofibroblasts disappear by apoptosis and a scar is formed. e | However, in many pathological situations, such as hypertrophic scar formation, myofibroblasts persist and continue to remodel the ECM, which results in connective-tissue contracture. In conclusion, myofibroblasts, far from being a 'bad' cell type, are functionally essential cells. It is their dysregulation that is the cause of tissue dysfunction.

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During the past 20 years, it has become generally accepted that the modulation of fibroblastic cells towards the myofibroblastic phenotype, with acquisition of specialized contractile features, is essential for connective-tissue remodelling during normal and pathological wound healing. Yet the myofibroblast still remains one of the most enigmatic o...

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... the model that is summarized in FIG. 9 pro- vides a framework for understanding connective-tis- sue contraction and contracture, several important aspects of this complex process remain to be deter- mined. Some of those points are discussed ...

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... It is noteworthy that tissue expansion results in the dermis thinned out (Agrawal and Agrawal, 2012), angiogenesis occurs (Zöllner et al., 2013), altered epithelial-mesenchymal interactions (Zhou et al., 2020, 1), chronic inflammation and fibroblastmyofibroblast differentiation (Kollmannsberger et al., 2018). The latter feature (differentiation of fibroblasts into myofibroblasts) is central to the excessive production of collagen-rich ECM (Tomasek et al., 2002;Tai et al., 2021) and dermal fibrosis He et al., 2021) under mechanical stretch. A further study verified that the papillary dermis exerts crucial functions in the favorable prognosis of skin regeneration under stretch (Tan et al., 2022). ...
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... A BDS capable of allowing bile to flow freely into the duodenum over a prolonged period has not yet been developed. It is unlikely that autologous tissue will resemble the native bile duct in the context of wound healing [40,50,51]. Stenting through the anastomotic site was effective in preventing narrowing[17, 48,49]. ...
... Bile duct regeneration must occur concurrently with wound healing [40,50,51]. Notably, the natural course of wound healing involves scar contraction. ...
... A BDS made of a non-bioabsorbable material that has been present in the body for a prolonged period retains its shape until the BDS is removed, but the lumen is prone to clogging by bile plugs [20][21][22]. Further, the anastomotic site with the native bile duct will be narrowed due to connective tissue growth [50,51]. Current bile duct regeneration methods using BDSs suggest that after the cell mass gathers around the foreign body and the BDS forms the shape of the bile duct, the cell mass regenerates as a bile duct after BDS removal [25]. ...
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