Transforming growth factor-β in stem cells and tissue homeostasis

Abstract

TGF-β 1-3 are unique multi-functional growth factors that are only expressed in mammals, and mainly secreted and stored as a latent complex in the extracellular matrix (ECM). The biological functions of TGF-β in adults can only be delivered after ligand activation, mostly in response to environmental perturbations. Although involved in multiple biological and pathological processes of the human body, the exact roles of TGF-β in maintaining stem cells and tissue homeostasis have not been well-documented until recent advances, which delineate their functions in a given context. Our recent findings, along with data reported by others, have clearly shown that temporal and spatial activation of TGF-β is involved in the recruitment of stem/progenitor cell participation in tissue regeneration/remodeling process, whereas sustained abnormalities in TGF-β ligand activation, regardless of genetic or environmental origin, will inevitably disrupt the normal physiology and lead to pathobiology of major diseases. Modulation of TGF-β signaling with different approaches has proven effective pre-clinically in the treatment of multiple pathologies such as sclerosis/fibrosis, tumor metastasis, osteoarthritis, and immune disorders. Thus, further elucidation of the mechanisms by which TGF-β is activated in different tissues/organs and how targeted cells respond in a context-dependent way can likely be translated with clinical benefits in the management of a broad range of diseases with the involvement of TGF-β.

Fig. 1. A model of integrin-mediated TGF-β activation during tissue/organ fibrosis.

Epithelial cells activate TGF-β by enriching the latent complex through αvβ8-RGD association and recruiting membrane-bound matrix metalloproteinases (e.g., MMP-14) in proximity for further proteolytic cleavage ①. Active TGF-β can act on resident fibroblasts, inducing its trans-differentiation into myofibroblasts, which are the major contributor to excessive ECM (e.g., collagen) deposition and fibrosis. The myofibroblasts can further activate TGF-β in a contractile force-dependent manner through the αvβ6-RGD association ②. The active TGF-β can in turn act on epithelial cells, fibroblasts, and myofibroblasts in a paracrine/autocine manner, and thus form a feed-forward loop for a sustained TGF-β activation and fibrogenesis. Of note, sustained activation of TGF-β can also induce the epithelial–mesenchymal transition (EMT) of epithelial cells with the assistance of integrin α3β1, which forms a complex with TGF-β type I and II receptors (TβRI/II) and E-cadherin, facilitating β-catenin/Smad2 complex formation and nuclear translocation. LAP: latency-associated peptide, LTBP: latent TGF-β binding protein, SLC: small latent complex, LLC: large latent complex.

Fig. 2. Activation of TGF-β recruits mesenchymal stem cells (MSCs) during bone remodeling.

TGF-β1 is released from the bone matrix and activated during osteoclast-mediated bone resorption, creating a gradient. TGF-β1 induces migration of MSCs to the bone remodeling sites to couple bone resorption and formation. The bone-resorptive microenvironment also provides signals (e.g., IGF-1) that direct the lineage-specific differentiation of MSCs. In addition, PTH orchestrates signaling of local factors and thus regulates cellular activities, including those of MSCs, T cells, and other PTH-responsive cells in the bone marrow to coordinate bone remodeling

Fig. 3. Common genetic disorders with aberrant TGF-β activity.

① Mutations in genes involved in the synthesis/assembly of extracellular matrix (ECM), e.g., Fibrillin-1 (FBN1), cause compromised matrix sequestration of the large latent complex of TGF-β and excessive TGF signaling, ultimately resulting in genetic disorders such as Marfan syndrome (MFS) and stiff skin syndrome (SSKS). ② Mutations in the region encoding latency-associated peptide (LAP) increase the release of active TGF-β, and cause Camurati–Engelmann disease (CED). ③ Mutations in genes encoding TGF-β type I and II receptors (TβRI/II) lead to compensatory synthesis of TGF-β ligand, and cause Loeys–Dietz syndrome (LDS). ④ Mutations in smads repressor, such as SKI, super-activate TGF-β signaling and causes Shprintzen–Goldberg syndrome (SGS) phenotypes. VSMC vascular smooth muscle cells