TGFβ signaling pathways in human health and disease

Abstract

Transforming growth factor beta (TGFβ) is named for the function it was originally discovered to perform-transformation of normal cells into aggressively growing malignant cells. It became apparent after more than 30 years of research, however, that TGFβ is a multifaceted molecule with a myriad of different activities. TGFβs are widely expressed with almost every cell in the human body producing one or another TGFβ family member and expressing its receptors. Importantly, specific effects of this growth factor family differ in different cell types and under different physiologic and pathologic conditions. One of the more important and critical TGFβ activities is the regulation of cell fate, especially in the vasculature, that will be the focus of this review.

Keywords: EndMT; RNAi; TGFβ; aneurysm; cell fate; endothelail cell; nanoparticle; smooth muscle cell.

FIGURE 1

Schematic of the TGFβ signaling pathway associated genetic connective tissue disorders. TGFβ initiates signaling by assembling receptor complexes that activate SMAD transcription factors. Phosphorylated Smad2/3 proteins form a trimeric complex with Smad4, translocate into the nucleus, and regulate gene expression. Different connective tissue diseases associated with specific TGFβ signaling effectors are indicated in black boxes.

FIGURE 2

The essential role of TGFβ signaling in connective tissue disease development. (A, B) A schematic diagram of TGFBR1 and TGFBR2 gene, exons and protein domain organization. As compared to TGFBR2, TGFBR1 contains a unique glycine/serine (GS) domain followed by the kinase domain. (C) TGFβ signaling components. (D) In type 2 LDS, missense mutations found in the serine/threonine kinase domain of TGFβR2 lead to decrease TGFβ signaling. (E–G) Clinical spectrum of findings in MFS, vEDS, and LDS.

FIGURE 3

The composition of aortic vessel wall. (A) Cross-sectional view of the aorta, with the boxed region showing the position of the vessel wall enlarged in panel (a). (a) A schematic of the three vessel layers: intima, media, and adventitia. Each layer has a unique cellular and extracellular matrix composition. (B) Endothelial cells undergo endothelial-to-mesenchymal transition in response to TGFβ stimulation. (C) Endothelial cell TGFβ/Smad signaling disrupts vascular homeostasis. (D) Summary of SMC cell fate transitions.

FIGURE 4

Endothelial-to-mesenchymal-transition associated diseases.

FIGURE 5

Diagram illustrating the sequence of events of aortic aneurysm development. (A, B) Externally or internally triggered inflammation and/or injury of the vessel wall can induce fate transitions of normal SMCs leading to potentiation of inflammation via production of pro-inflammatory molecules, the appearance of SMC-derived bone- and cartilage-producing cells as well as macrophage-like cells, leading to disorganization of the aortic extracellular matrix. These changes result in the weakening of the aortic wall, resulting in its dilation and aneurysm formation. (C) Events responsible for calcification, elastin breaks, and inflammation of the TAA include i) upregulation of the stem cell pluripotency gene KLF4 due to the loss of TGFβ signaling input, ii) reprogramming of SMC to mesenchymal stem cell (MSCs) state by KLF4, iii) clonal expansion of a disease-prone subsets, iv) tri-lineage differentiation of MSCs into osteoblasts-, chondrocytes-, adipocytes-like cells, and appearance of SMC-derived macrophage-like cells.

FIGURE 6

TGFβ blocking drugs in preclinical and clinical trials.