Development of functional resident macrophages in human pluripotent stem cell-derived colonic organoids and human fetal colon

Cell Stem Cell. 2023 Nov 2;30(11):1434-1451.e9. doi: 10.1016/j.stem.2023.10.002.


Most organs have tissue-resident immune cells. Human organoids lack these immune cells, which limits their utility in modeling many normal and disease processes. Here, we describe that pluripotent stem cell-derived human colonic organoids (HCOs) co-develop a diverse population of immune cells, including hemogenic endothelium (HE)-like cells and erythromyeloid progenitors that undergo stereotypical steps in differentiation, resulting in the generation of functional macrophages. HCO macrophages acquired a transcriptional signature resembling human fetal small and large intestine tissue-resident macrophages. HCO macrophages modulate cytokine secretion in response to pro- and anti-inflammatory signals and were able to phagocytose and mount a robust response to pathogenic bacteria. When transplanted into mice, HCO macrophages were maintained within the colonic organoid tissue, established a close association with the colonic epithelium, and were not displaced by the host bone-marrow-derived macrophages. These studies suggest that HE in HCOs gives rise to multipotent hematopoietic progenitors and functional tissue-resident macrophages.

Keywords: endothelial-to-hematopoietic transition; hemogenic endothelium; human colonic organoids; tissue-resident macrophages.

Publication types

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

MeSH terms

  • Animals
  • Colon
  • Hematopoietic Stem Cells
  • Humans
  • Macrophages
  • Mice
  • Organoids
  • Pluripotent Stem Cells*