Intestinal myofibroblasts: targets for stem cell therapy

Abstract

The subepithelial intestinal myofibroblast is an important cell orchestrating many diverse functions in the intestine and is involved in growth and repair, tumorigenesis, inflammation, and fibrosis. The myofibroblast is but one of several α-smooth muscle actin-positive (α-SMA(+)) mesenchymal cells present within the intestinal lamina propria, including vascular pericytes, bone marrow-derived stem cells (mesenchymal stem cells or hematopoietic stem cells), muscularis mucosae, and the lymphatic pericytes (colon) and organized smooth muscle (small intestine) associated with the lymphatic lacteals. These other mesenchymal cells perform many of the functions previously attributed to subepithelial myofibroblasts. This review discusses the definition of a myofibroblast and reconsiders whether the α-SMA(+) subepithelial cells in the intestine are myofibroblasts or other types of mesenchymal cells, i.e., pericytes. Current information about specific, or not so specific, molecular markers of lamina propria mesenchymal cells is reviewed, as well as the origins of intestinal myofibroblasts and pericytes in the intestinal lamina propria and their replenishment after injury. Current concepts and research on stem cell therapy for intestinal inflammation are summarized. Information about the stem cell origin of intestinal stromal cells may inform future stem cell therapies to treat human inflammatory bowel disease (IBD).

DLL4 promotes continuous adult intestinal lacteal regeneration and dietary fat transport

“…As expected, NG2 staining identified pericytes closely associated with villus blood capillaries ( Figure 1C) and a dense network of cells between villus epithelial cells and blood capillaries, which are most likely subepithelial myofibroblasts (20). Although previous studies in tissue sections suggested the presence of vascular smooth muscle cells (SMCs) on lacteals and blood capillaries (21,22), we failed to confirm this observation in our 3D analysis ( Figure 1, D and E). Instead, in agreement with high villus contractility (23), we observed tree-like smooth muscle fibers (Figure 1, D-F), identified by α-smooth muscle actin (αSMA) and desmin staining (Supplemental Figure 1C).…”

“…We next measured lacteal length as a percentage of the blood capillary cage length and the number of filopodia/lacteal. Interestingly, relative lacteal length was constant in the different intestinal segments (60%-70% of villus length), and the number of lacteal blasts (21). The SMC network extends throughout the entire villus length and is focally in close proximity to lacteals (Figure 1, E and F), whereas the terminal ends of SMC fibers are closely associated with villus blood capillaries ( Figure 1G).…”

Distinct levels of Sox9 expression mark colon epithelial stem cells that form colonoids in culture

“…The conditions that support generation of organoids from IESCs were modified to include exogenously supplied recombinant WNT3a, as well as an underlying layer of MFs derived from embryonic murine intestine. Pericryptal MFs have been implicated in the support of epithelial growth and development by secreting mitogens and morphogens in the IESC zones (23,32). These new conditions supported development of mature colonoids, which formed from isolated whole crypts (Fig.…”

Epimorphin deletion inhibits polyposis in theApcmin/+mouse model of colon carcinogenesis via decreased myofibroblast HGF secretion

“…The crypts of Lieberkuhn contain stem cells that give rise to proliferating daughter/progenitor cells, which differentiate into the four major cell types of the intestine. Surrounding stromal cells, including myofibroblasts, play a critical role in modulating epithelial cell proliferation (19,22) and carcinogenesis (34). Stromal myofibroblasts that encircle the intestinal crypts contribute to maintaining the normal stem cell niche (19,26,32,37), and tumor-associated myofibroblasts play a critical role in promoting epithelial carcinogenesis, in part by regulating cancer stem cells (27,31,34) and enhancing tumor growth (2,16).…”