The Dual Niche Roles For The Twist2 Mesenchymal Lineage In Intestinal Stem Cell Homeostasis And Tissue Repair

The intestinal villi,site of nutrient absorption,is a fast-turnover tissue prone to injury caused by radiation,food-borne pathogens,and the intestinal microbiota.The villi are renewed and repaired by intestinal stem cells(ISCs),which rely on their niches.The mesoderm-derived mesenchymal cells(MCs),Paneth cells,myofibroblasts and enterocytes are located near ISCs,generally believed to be the niche and provide signaling molecules such as Wnts and BMPs.However,to date the niches controlling ISC homeostasis and regeneration remain disputed and unclear.Our lineage tracing,cell depletion,and gene knockout experiments revealed that the Twist2 intestinal mesenchymal lineage provides dual niche functions for ISCs during villus homoeostasis and repair.Twist2 lineages were present in the intestinal laminar propria,localized near Lgr5+ ISCs and surrounded the crypts.Depletion of Twist2-labeled cells in mice significantly disrupts villus homeostasis and affects the differentiation and regeneration of Lgr5+ intestinal stem cells.Moreover,the intestinal Twist2 lineage MCs expressed some of the MSC markers and retain the major features of MSCs.Upon radiation-induced injury,this lineage and its stem cells quickly transdifferentiated into Paneth cells,which secrete anti-microbial proteins to establish inflammation-restricted environment to promote ISC regeneration and villus repair.Blocking Wnts secretion from this lineage perturbs ISC homeostasis and villus development.Moreover,transdifferentiation to Paneth cells requires Wnt/?-Catenin signaling.And antibiotics pretreatment partially rescued the inflammation and regeneration defects in the conditional knock out of Wls or Ctnnb1(expression of ?-Catenin)mice.Finally,systematically-delivered Twist2 bone marrow mesenchymal stem cells could also be transdifferentiated into Paneth cells and promote ISC regeneration and villus repair.Thus,the Twist2 mesenchymal lineage functions as niches for ISC homeostasis and regeneration via distinct mechanisms.The gastrointestinal tract is responsible for food digestion and absorption.The muscularis propria propels the foodstuff through the GI tract and defects in intestine motility may cause obstruction disorders.Our present genetic studies identified non-receptor tyrosine kinase c-Abl as an important regulator of the muscularis propria homeostasis and a risk factor for rectal prolapse.Mouse deficient for c-Abl showed defects in the muscularis propria of gastrointestinal tract and older c-Abl^-/-mice developed megaesophagus and rectal prolapse.Inhibition of c-Abl with imatinib mesylate,an anti-CML drug,or ablation of c-Abl using Prx1-Cre,which marks smooth muscle cells,recapitulated most of the muscularis propria phenotypes.The pro-aging protein p16Ink4 a deficiency partially rescued the neonatal lethality of c-Abl^-/-mice,but been useless in the megaesophagus nor rectal prolapse.The pathogenesis of rectal prolapse was attributable to overproliferation of smooth muscle cells,which was caused by enhanced ERK1/2 activation.Mouse deficient for c-Abl led to enhanced ERK1/2 activation on rectum sections.Administration of ERK inhibitor U0126 impeded imatinib mesylate-induced increase in smooth muscle cell proliferation,and prevent the development of rectal prolapse in c-Abl deficient mice.These results reveal a role for c-Abl-regulated smooth muscle proliferation in the pathogenesis of rectal prolapse,and imply that long-term use of imatinib mesylate may cause gastrointestinal problems in patients while ERK inhibitor may be effective in treating rectal prolapse.