TGF-β mainly signals through the Smad pathway, and regulates inflammation, morphogenesis, angiogenesis, collagen generation, and cell differentiation. The TGF-β/Smad pathway is closely related to scarring and fibrosis, and its activation can induce excessive fibroblast proliferation and excessive ECM deposition. This pathway is initiated by the phosphorylation of Smad2 and Smad3 via the TGF-β receptor protein, which forms complexes with Smad4 and translocates to the nucleus. This translocated heteropolymer complex can regulate profibrotic genes and promote the differentiation of fibroblasts into myofibroblasts [
15]. This complex is dephosphorylated by phosphatase, causing Smad4 to move back into the cytoplasm, where it forms another complex. If the TGF-β receptor is still active, the attenuation of this pathway can occur through the activation of Smad6 and Smad7, which bind to the TGF-β receptor and dephosphorylate Smad2 and Smad3. In addition, Smad7 can also introduce ubiquitin ligase into the receptor complex. TGF-β1 induces the expression of Smad7, which functions as a negative feedback loop. Overexpression of Smad7 causes cells to lose their responsiveness to TGF-β1, which has anti-inflammatory effects even in inflammatory diseases. TGF-β is a multifunctional growth factor, because the expression of different isomers has different effects on the wound. During wound healing, TGF-β promotes the formation of connective tissue, and regulates inflammation, proliferation, and re-epithelialization, Its three isomers, TGF-β1, TGF-β2, and TGF-β3, play important roles in wound contraction and scar formation. TGF-β1 is the most prevalent and biologically relevant isomer and is associated with excessive scarring and fibrosis in wounds. Although TGF-β3 is homologous to TGF-β1, it has an antifibrotic effect on skin tissue. In the early stage of wound healing, the concentration of TGF-β3 is higher than that of TGF-β1, and the concentration of TGF-β1 increases after epithelization [
5]. TGF-β is a chemokine produced by endothelial cells that promotes the production of other growth factors, such as EGF and insulin-like growth factor (IGF). In addition, the EGF and TGF-β1 pathways can stimulate each other, and their interaction can inhibit the proliferation of endothelial cells. When bound to specific ligands on cell surface receptors, TGF-β promotes the production of keratinocytes, fibroblasts, neutrophils, and macrophages, and then triggers the release of proinflammatory cytokines such as IL-1α and β, IL-6, and TNF-α. Second, TGF-β can directly induce the expression of α smooth muscle actin (α-SMA) in fibroblasts, thus promoting their differentiation into myoblasts. TGF-β2 has similar activity to TGF-β1, and its downregulation can reduce scar formation [
5]. Wound treatment with antibodies against TGF-β1 and TGF-β2 has been shown to restore the skin structure to a state similar to that of uninjured skin [
16], suggesting that inhibiting or downregulating TGF-β1 and TGF-β2 may reduce the occurrence of scarring. In addition, TGF-β1 expression levels were different between youths and adults, and the expression levels in adults were higher. Penn's research on the role of TGF-β1 in wound healing suggests that changes in TGF-β1 are related to the severity of scarring, and TGF-β1 upregulates collagen genes and genes that promote collagen expression, such as membrane proteins [
17]. In summary, TGF-β activity may contribute to wound contraction and closure, and is also associated with severe scarring and increased fibrosis. In recent years, more and more studies have focused on the uterus. Yao et al. [
18] found that BMSC-derived Exo may promote endometrial repair through the TGF-β1/Smad signalling pathway. There is also evidence to support that TGF-β1 is strongly associated with the onset and progression of intrauterine adhesion (IUA) and is considered an early risk factor for disease recurrence [
19]. In addition, it has been found that TGF increases the proliferative capacity of endometrial and muscle cells, promotes the regeneration of the microvascular system, and restores the ability of the endometrium to receive embryos and support their development to a viable stage, through the transplantation of collagen/BM-MSCs constructs [
20]. Further study of TGF-β, its downstream signals and the role of crosstalk signals may provide new therapeutic targets for reducing scarring and fibrosis.