Table 3.

Main signaling pathways in soft tissue regeneration

Signaling pathways	Major characteristics and functions	Applications in bone regeneration
JNKs	JNKs are known to be significant molecules mediating the intracellular response of stem cells to many different types of stimuli present in the external cellular microenvironment [115, 116]. JNK function is essential for building a delicate balance between cell death and stem cell survival in order to promote soft tissue repair, remodeling, and regeneration [117]	In a mouse wounding model, transplantation of preconditioned stem cells was capable of enhancing soft tissue regeneration with a robust antioxidant defensive mechanism through activation of JNKs signaling [118] Activation of JNK signaling promotes the differentiation of MSCs into keratinocytes and promotes tissue regeneration in mice [119, 120]
Akt	Akt activation occurs following Thr308 and Ser473 residues phosphorylation, and active Akt is capable of controlling multiple cellular regulatory processes, ranging from cell survival to cell metabolism [121–123]	Activation of PI3K/Akt/mTOR signaling enhances soft tissue repair and regeneration in the mouse wounding model [121, 122, 124]
Wnt	The role of Wnt/β-catenin signaling in soft tissue homeostasis and regeneration is well-documented. Wnt/β-catenin signaling is critically involved in the regulation of stem cell function and tissue repair, as well as in the progress of chronic inflammatory diseases [125, 126]. Within the nucleus, β-catenin binds to T-cell factor transcription enhancers, thus promoting the transcription of specific genes and a specific Wnt/β-catenin transduction outcome [127]	Activation of this β-catenin-dependent pathway can enhance the proliferation and function of stem cells such as ESCs and MSCs, markedly promoting soft tissue regeneration in mice [128–130]
Nrf2	Nrf2 is the primary mediator of active redox homeostasis, and it was previously found that some biofactors ameliorate cellular oxidative stress and enhance stem cell function, accelerating tissue repair by promoting Nrf2 activation [131]. The important role of Nrf2 in regeneration is the prevention of ROS accumulation in damaged tissues and activation of the antioxidant defense system [132]	In the mouse wounding model, Nrf2 signaling was demonstrated to act a protective role against cellular ROS via activation of the antioxidative system during tissue regeneration [133, 134] Nrf2 deficiency impedes corneal epithelial wound healing in a Nrf2 knockout (Nrf2-KO) murine model [119]
ERK1/2	Erk1/2 is activated by phosphorylation of various growth factors, ion rays, and hydrogen peroxide and affects the function of transcription factors such as c-MyC, c-FOS, c-Jun, ATF, NF-κB and AP-1. Erk1/2 promotes the transcription and expression of genes, which is closely related to cell proliferation and differentiation [135]	Visfatin could enhance wound repair and regeneration via activation of ERK1/2 signaling pathway in mice [136]
JAK	JAK/STAT signaling plays a prominent role in cellular stress, inflammatory response, and wound regeneration and regulates the physiological balance of the body [137]. This pathway is not only involved in cell proliferation, differentiation, and apoptosis but also related to immunomodulatory biological processes [138]	Local injection of JAK or STAT inhibitor could markedly delay wound repair and regeneration in mice [138]
HIF-1α	In diabetes, the suppression of HIF-1α could lead to a failure of the wound to activate VEGF in response to soft tissue ischemia, resulting in impaired wound angiogenesis and regeneration [139]	Injection of roxadustat is capable of accelerating diabetic wound healing via activating the HIF-1α/VEGF/VEGFR2 signaling in diabetic rat model [139]

ESCs embryonic stem cells, JNKs c-Jun N-terminal Kinases, mTOR mammalian target of rapamycin, Nrf2 nuclear factor erythroid 2-associated factor 2, ROS reactive oxygen species, STAT signal transducer and activator of transcription, VEGFR2 vascular endothelial growth factor receptor 2, MSCs mesenchymal stem cells, ESCs embryonic stem cells, ROS reactive oxygen species, c-MyC v-myc avian myelocytomatosis viral oncogene homolog, c-FOS serum response factor, c-Jun proto-oncogene, ATF activating transcription factor, NF-κB nuclear factor kappa-B, AP-1 activator protein 1, HIF-1α hypoxia inducible factor-1α