Graded BMP signaling within intestinal crypt architecture directs self-organization of the Wnt-secreting stem cell niche

Judith Kraiczy; Neil McCarthy; Ermanno Malagola; Guodong Tie; Shariq Madha; Dario Boffelli; Daniel E Wagner; Timothy C Wang; Ramesh A Shivdasani

doi:10.1016/j.stem.2023.03.004

Graded BMP signaling within intestinal crypt architecture directs self-organization of the Wnt-secreting stem cell niche

Cell Stem Cell. 2023 Apr 6;30(4):433-449.e8. doi: 10.1016/j.stem.2023.03.004.

Authors

Judith Kraiczy¹, Neil McCarthy¹, Ermanno Malagola², Guodong Tie³, Shariq Madha³, Dario Boffelli⁴, Daniel E Wagner⁵, Timothy C Wang², Ramesh A Shivdasani⁶

Affiliations

¹ Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Departments of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
² Division of Digestive and Liver Diseases, Department of Medicine and Irving Cancer Research Center, Columbia University Medical Center, New York, NY 10032, USA.
³ Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁴ Institute for Human Genetics and Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94158, USA.
⁵ Department of Obstetrics, Gynecology and Reproductive Science and Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
⁶ Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Departments of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: ramesh_shivdasani@dfci.harvard.edu.

Abstract

Signals from the surrounding niche drive proliferation and suppress differentiation of intestinal stem cells (ISCs) at the bottom of intestinal crypts. Among sub-epithelial support cells, deep sub-cryptal CD81⁺ PDGFRA^lo trophocytes capably sustain ISC functions ex vivo. Here, we show that mRNA and chromatin profiles of abundant CD81^- PDGFRA^lo mouse stromal cells resemble those of trophocytes and that both populations provide crucial canonical Wnt ligands. Mesenchymal expression of key ISC-supportive factors extends along a spatial and molecular continuum from trophocytes into peri-cryptal CD81^- CD55^hi cells, which mimic trophocyte activity in organoid co-cultures. Graded expression of essential niche factors is not cell-autonomous but dictated by the distance from bone morphogenetic protein (BMP)-secreting PDGFRA^hi myofibroblast aggregates. BMP signaling inhibits ISC-trophic genes in PDGFRA^lo cells near high crypt tiers; that suppression is relieved in stromal cells near and below the crypt base, including trophocytes. Cell distances thus underlie a self-organized and polar ISC niche.

Keywords: PDGFRA+ mesenchymal cells; colonic crypts; intestinal Wnt source; intestinal crypt structure and function; intestinal stem cell niche; mesenchymal niche compartments; trophocytes.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation
Cell Proliferation
Intestinal Mucosa* / metabolism
Intestines
Mice
Signal Transduction
Stem Cell Niche*

Abstract

Publication types

MeSH terms

Grants and funding