Transforming Growth Factor-β and Endoglin Signaling Orchestrate Wound Healing

Abstract

Physiological wound healing is a complex process requiring the temporal and spatial co-ordination of various signaling networks, biomechanical forces, and biochemical signaling pathways in both hypoxic and non-hypoxic conditions. Although a plethora of factors are required for successful physiological tissue repair, transforming growth factor beta (TGF-β) expression has been demonstrated throughout wound healing and shown to regulate many processes involved in tissue repair, including production of ECM, proteases, protease inhibitors, migration, chemotaxis, and proliferation of macrophages, fibroblasts of the granulation tissue, epithelial and capillary endothelial cells. TGF-β mediates these effects by stimulating signaling pathways through a receptor complex which contains Endoglin. Endoglin is expressed in a broad spectrum of proliferating and stem cells with elevated expression during hypoxia, and regulates important cellular functions such as proliferation and adhesion via Smad signaling. This review focuses on how the TGF-β family and Endoglin, regulate stem cell availability, and modulate cellular behavior within the wound microenvironment, includes current knowledge of the signaling pathways involved, and explores how this information may be applicable to inflammatory and/or angiogenic diseases such as fibrosis, rheumatoid arthritis and metastatic cancer.

Keywords: TGFβ; angiogenesis; endoglin; progenitor cells; stem cells; wound healing.

Figure 1

Schematic representation of the cellular mechanisms that pattern acute wound healing. The four main phases of wound healing are hemostasis, inflammation, proliferation, and remodeling. Different cell types are involved in regulating biomechanical and biochemical functions during these phases of wound healing. The main source for these cell types are different stem cell niches. Hematopoietic stem cells (HSCs), platelets, neutrophils, and monocytes regulate hemostasis and inflammation. Mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs), pericytes, vascular smooth muscle cells (VSMCs), endothelial cells (ECs), and fibroblasts regulate angiogenesis. Epithelial mesenchymal transitions (EMT), fibroblasts and fibrocytes regulate collagen, and extracellular matrix (ECM) production. Epidermal stem cells (ESCs) and keratinocytes regulate epithelialization. Fibroblasts and proteolytic enzymes regulate remodeling in the final phase of wound healing.

Figure 2

Schematic representation of the TGF-β superfamily signaling pathways and cellular regulation during the wound healing process. TGF-β Superfamily proteins transforming growth factor beta (TGF-β), growth differentiation factors (GDFs), activin, and bone morphogenetic proteins (BMPs) bind to Type I, II, and III receptor complexes. This leads to activation of intracellular R-Smad, Co-Smad, and I-Smad signaling cascades. These interactions regulate hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), and endothelial progenitor cells (EPCs) from the stem cell niche. They also regulate monocytes, fibroblasts, endothelial cells (ECs), keratinocytes, and epithelial mesenchymal transitions (EMT) during wound healing.

Figure 3

Hypothetical model of Endoglin structure and function. Endoglin, also called CD105, is a type III auxiliary coreceptor (TβRIII). L-Endoglin and S-Endoglin are two isoforms of Endoglin. L-Endoglin shown in this figure is a 68,051 Da homodimeric transmembrane glycoprotein that binds to TGF-β1, TGF-β2, activin, BMP-2, and BMP-7 by associating with the TGF-β type II receptors (ActRII, ActRIIB, ALK1, ALK2, ALK3, ALK5, ALK6, BMPRII, and TβRII). Intranuclear events show that Sp1 regulates Endoglin transcription by interacting with other factors in the hypoxic environment. TGF-β1 and β3 regulate intracellular Smads (Smad1/5, Smad 2/3, and Smad4) via the TGF-β receptor complex, which regulates cell proliferation, adhesion, and permeability. Intracytoplasmic events show that Smad6 inhibits phosphorylation of Smad1/5 and Smad7 inhibits phosphorylation of Smad2/3. TGF-β signaling through Endoglin induces inhibition of caspases 3 and 8 and therefore inhibition of apoptosis. Endoglin interaction with ZRP-1, Zyxin, and Tctex2b regulates cell adhesion and migration. Thrombin induces internalization of Endoglin TGF-βRII complex by endocytosis.

Figure 4

Schematic representation of Endoglin expression in different cell types during the wound healing process. Endoglin is expressed on stem cells and proliferating cells, and is an expression marker for MSCs, HSCs, and megakaryocyte–erythroid progenitors. Eng+9 and Eng+7 function as potent hematoendothelial enhancers and Endoglin is expressed in proliferating endothelial cells, VSMCs, pericytes, and basal keratinocytes. The functional role of endoglin on all these cell types in wound healing is not currently well understood.