Lymphatics act as a signaling hub to regulate intestinal stem cell activity

Area of Science:

• Gastroenterology
• Stem Cell Biology
• Lymphatic Biology

Background:

• Barrier epithelia rely on resident stem cells for tissue homeostasis, defense, and repair.
• Intestinal stem cells (ISCs) are crucial for continuous intestinal tissue turnover, responding to their local microenvironments (niches).
• The intricate communication pathways within intestinal niches remain incompletely understood.

Purpose of the Study:

• To investigate the role of the intestinal crypt base microenvironment in maintaining intestinal stem cells (ISCs).
• To identify novel signaling pathways and cellular components within the ISC niche.
• To elucidate the function of the lymphatic system in intestinal stem cell regulation.

Main Methods:

• In vivo loss-of-function studies and lymphatic-organoid co-cultures were employed to assess crypt lymphatic function.
• Single-cell and spatial transcriptomics were utilized to map niche components and signaling.
• BayesPrism and SpaceFold were applied for deconvolution of gene expression and high-resolution niche mapping.

Main Results:

• A lymphatic network was identified at the intestinal crypt base, closely associated with ISCs.
• Crypt lymphatics were shown to maintain ISCs and prevent their premature differentiation.
• Lymphatics were revealed as a central signaling hub, with identified signals including WNT2, R-SPONDIN-3, and REELIN.

Conclusions:

• The intestinal crypt base harbors a lymphatic network crucial for intestinal stem cell (ISC) maintenance.
• Lymphatic-derived signals, including WNT2, R-SPONDIN-3, and REELIN, directly regulate ISC regenerative potential.
• This discovery highlights lymphatics as a key regulator of intestinal stem cell function and tissue repair.