The cellular niche for intestinal stem cells: a team effort

Abstract

The rapidly self-renewing epithelium in the mammalian intestine is maintained by multipotent intestinal stem cells (ISCs) located at the bottom of the intestinal crypt that are interspersed with Paneth cells in the small intestine and Paneth-like cells in the colon. The ISC compartment is also closely associated with a sub-epithelial compartment that contains multiple types of mesenchymal stromal cells. With the advances in single cell and gene editing technologies, rapid progress has been made for the identification and characterization of the cellular components of the niche microenvironment that is essential for self-renewal and differentiation of ISCs. It has become increasingly clear that a heterogeneous population of mesenchymal cells as well as the Paneth cells collectively provide multiple secreted niche signals to promote ISC self-renewal. Here we review and summarize recent advances in the regulation of ISCs with a main focus on the definition of niche cells that sustain ISCs.

Spatial organisation and homeostasis of epithelial lineages at the gastroesophageal junction is regulated by the divergent Wnt mucosal microenvironment

“…Adult mucosal tissue regeneration and maintenance depends on the balanced action of tissue-specific stem cells self-renewal, proliferation, differentiation and cell-fate commitment. The tissue microenvironment, including stromal and immune cells, is critical in regulating stem cell regeneration and maintaining normal homeostasis 2,33,37,38 . During tissue injury, the tissue microenvironment reprograms for the restoration of damaged tissue 39 .…”

Telocytes: An Emerging Component of Stem Cell Niche Microenvironment

“…[61][62][63] The self-renewal, long-term maintenance, and differentiation capabilities of ISCs rely on the intricate interaction among different intracellular pathways and extracellular signals provided by the neighboring epithelial and mesenchymal cells constituting the specialized niche microenvironment (i.e., the ISC niche). 64,65 Consistent with this notion, in vitro expansion and growth of CBC ISCs into organoids containing proliferating and differentiated epithelial cells is, indeed, supported only if factors partly provided in vivo by the mesenchymal niche are administered. 64,66 Among these factors, the canonical Wnt/R-spondin system represents one of the major mitogens.…”

“…81 Finally, two other pathways involved in the regulation of ISC function are represented by the Hippo and the Hedgehog (Hh) signaling pathways. 65 Collectively, the activity of all these signalings creates reverse gradients along the crypt-villus axis to orchestrate selfrenewal and differentiation of ISCs.…”

Identifying key regulators of the intestinal stem cell niche

“…Telocytes have recently been identified as key controllers of the ISC niche [ 42–44 ] but share several features with sub-epithelial myofibroblasts (SEMFs). Due to recent advances in imaging, single-cell sequencing, and the identification of various sub-populations and locations of these cell types, the nomenclature that categorises these populations as discrete is still being defined [ 45 , 46 ]. Telocytes are thought to be distinct from SEMFs, smooth muscle and interstitial cells of Cajal (ICC) in that they express CD34 [ 47 ], PDGFRα [ 48 ], the Foxl1 transcription factor [ 42 ] and in the colon Gli1 [ 44 ], but don't express Acta2 (α-SMA), Myh11 [ 42 ] or c-Kit [ 49 ].…”

“…Telocytes are thought to be distinct from SEMFs, smooth muscle and interstitial cells of Cajal (ICC) in that they express CD34 [ 47 ], PDGFRα [ 48 ], the Foxl1 transcription factor [ 42 ] and in the colon Gli1 [ 44 ], but don't express Acta2 (α-SMA), Myh11 [ 42 ] or c-Kit [ 49 ]. SEMFs express Myh11 and Acta2 but are located similarly to telocytes adjacent to the intestinal epithelium and a sub population also express the telocyte markers Foxl1, Gli1 [ 46 ] and PDGFRα [ 50 ]. SEMFs have been shown to regulate intestinal and gastric organoid growth and differentiation [ 51 , 52 ] in vitro and secrete factors that stimulate epithelial cell proliferation in vivo [ 53 ].…”