Wnt-act (Wnt2b, 5a, Rspo3); Wnti (Sfrp1, Dkk3); BMPi (Chrdl1, Grem 1); BMPs (BMP4, 5, 6, 7); Others (Fgf7, Hgf, Igf1, Igfbp5, Pgf, Ctgf)
As an essential source of Wnt signals for ISCs.
Ablation of Foxl1+ cells in Foxl1-hDTR or Foxl1-cre; Rosa26-iDTR mice causes abrupt cessation of ISC proliferation; Deletion of Porcn in Foxl1-creERT2 mice causes rapid decline of Wnt activity and crypt loss.
Gli1+ mesenchymal cells
Wnt-act (Wnt2, 2b, and 4; Rspo3); Wnti (Sfrp1)
An essential Wnt source in colon and a reserve Wnt source in SI; Responsive to damage-induced intestinal regeneration
Deletion of Wls in Gli1-creERT2 mice causes ISC loss in colon over time; Deletion of Wls in Vilin-creERT2 and GLI1-creERT2 combined mice causes reduced ISC proliferation in SI over time; ScRNA-seq data suggests the expansion of Gli+ cells following epithelial damage.
(Degirmenci et al., 2018)
Sustain ISCs in vivo; promote ISC expansion in vitro.
Ablation of Grem1+ cells in Grem1–creERT2; Rosa26–iDTR mice causes rapid ISC loss; The Grem1+ trophocytes can support enteroid growth without exogenous Wnt/Rspo and BMPi factors.
(McCarthy et al., 2020)
CD34+GP38+ mesenchymal cells
Wnt-act (Wnt2b, Rspo1); BMPi (Grem1); Others (Areg, Fgf7, Fgf10, Ptgs2 and Col1a1);
Maintain ISCs in vitro; contribute to intestinal repair after injury.
CD34+Gp38+ cells promote ISC maintenance in intestinal organoids; these cells are rapidly expanded in DSS-mediated colitis.
(Stzepourginski et al., 2017)
PDGFR-α+ pericryptal stromal cells
Wnts and Rspo3
As critical source of Wnts and Rspo3 for ISC self-renewal.
Deletion of Porcn in PdgfRα-cre mice blocks crypt formation; Deletion of Rspo3 in PdgfRα-cre mice causes decreased crypt WNT/β-catenin signaling and predisposes to DSS-induced colitis.
(Greicius et al., 2018)
Wnt2b and Wnt4
Required for gut regeneration.
Deletion of Wls using Cspg4-cre mice causes reduced ISCs and comprised regeneration following irradiation.
(Kim et al., 2020)
BMPi (Grem1); Wnt-act (Wnt2b, and Rspo3); Others (Sema3).
Support the organoid growth.
Co-culture of CD90+ crypt fibroblasts supports organoid growth in R-spondin-reduced medium;
(Karpus et al., 2019)
Wnt-act (Rspo3); Wnti (Dkk3);
Coculture of myofibroblasts and SI crypts supports long-term growth without Rspo1.
(Lei et al., 2014)
Deletion of Porcn using Myh11-creERT2 and/or Villin-creERT2 lines all fails to disrupt crypt proliferation or Wnt pathway activity;
(San Roman et al., 2014)
Endothelial, immune, smooth muscle cells, macrophages, etc.
Wnt-act (Rspo3), Wnti, BMPi and NOTCH ligands (Dll1 and Dll4) in many of these cells