Cellular and molecular mechanisms of intestinal fibrosis

Table 1 Extracellular matrix molecules involved in wound repair and fibrosis

Collagens	Fibrillar type collagens I-III-V
	Non-fibrillar collagen type IV
Glycoproteins	Laminin
	Entactin/nidogen
	Fibronectin
	Tenascin
	Sparc/BM40
	Thrombospondin
Proteoglycans	Glycosaminoglycans (hyaluronic acid)
	Heparan sulfate
	Chondroitin sulfate
	Perlecan
ECM-modifying proteins	Matrix metalloproteinases
	Tissue inhibitor of metalloproteinases

ECM: Extracellular matrix.

Table 2 Cell types involved in intestinal fibrosis

Cell type	Positive markers
Fibroblasts	Vimentin, FSP-1, N-cadherin (high), collagen type I, prolyl 4-hydroxylase
Intestinal subepithelial myofibroblasts	Vimentin, α-SMA, cadherin-11, FSP-1, collagen type I
Interstitial cells of Cajal	Vimentin, c-Kit receptor
Smooth muscle cells	Vimentin (low), α-SMA, Desmin, collagen type I
Stellate cells	Vitamin A, GFAP, α-SMA
Pericytes	a-SMA, desmin (low), MCSP,
	RGS5, PDGFR-β
	CD80, CD86, CD 13, CD90
	ANG I and II, ET-1, collagen type I
Epithelial cells	E-cadherin, cytokeratins
Endothelial cells	CD31, vWF, VE-cadherin, N-cadherin (low), vimentin (low)
Bone marrow stem cells
Hematopoietic stem cells	CD45, CD34, CD14
Mesenchymal stem cells	CD105, CD73, CD44, CD71, CD90
Fibrocytes	CD45, CD34, CD11, CD13, CD14,
	CD80, CD86, collagen type I, α-SMA

FSP-1: Fibroblast specific protein 1; MCSP: Melanoma chondroitin sulfate proteoglycan; RGS5: Regulator of G protein signaling-5; GFAP: Glial fibrillary acidic protein; α-SMA: α-smooth-muscle actin; VE-cadherin: Vascular endothelial cadherin; vWF: von Willebrand factor; cKit: Tyrosine-protein kinase kit or CD117; ANG I and II: Angiotensin I and II; ET-1: Endothelin-1; CD: Cluster of differentiation. High and low indicate level of expression.

Table 3 Predominant pro-fibrotic cytokines

Cytokines	Role in fibrosis	Ref.
IL-1/IL-33	Activate myofibroblasts	[144,146]
	Stimulate TGF expression	[145]
	Regulate chemokines, cytokines and MMPs secretion	[144]
IL-4/IL-13	Activate myofibroblasts	[147]
	Increase deposition of collagen I, III and IV	[148]
	Induce production of latent TGF-β and activate TGF-β	[152,153]
	Promote fibrocyte differentiation	[154]
IL-6	Stimulates proliferation of fibroblasts	[157]
	Modulates TGF-β and TGF-βRII	[156]
	Its neutralization improves fibrosis	[155]
IL-21/IL-22	Stimulate the expression of IL-4, IL-13 and IL-17	[159]
	Increase secretion of ECM degrading enzymes	[160]
	Maintain the integrity of the epithelial barrier	[161]
	Inhibit deposition of collagen	[163]
IL-17/IL-23	Maintain chronic inflammation in the gut	[143]
	Induce activation and proliferation of myofibroblasts	[165]
	Stimulate deposition of collagen	[164]
TNFα	Stimulates intestinal myofibroblast proliferation	[170]
	Stimulates deposition of collagen	[171]
	Inhibits collagen degradation through TIMP-1 induction	[172,173]

TNF: Tumor necrosis factor; ECM: Extracellular matrix; IL: Interleukin; TGF-β: Transforming growth factor-β; TIMPs: Tissue inhibitors of metalloproteinases; MMPs: Matrix metalloproteinases.