Table 2 The cellular origin of ISC niche signals in the mesenchymal compartment

Foxl1⁺ telocytes

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.

(Aoki et al., 2016; Shoshkes-Carmel et al., 2018)

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)

CD81⁺PDGFR-α^lo trophocytes

BMPi (Grem1)

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)

Cspg4⁺ pericyte-like

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)

CD90⁺ fibroblasts

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)

Myofibroblasts

Wnt-act (Rspo3); Wnti (Dkk3);

Uncertain

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

N. D

N. D.

(Bauché et al., 2018; Hansen et al., 2019; Ogasawara et al., 2018)