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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE240363 | GEO | 2023/10/31

REPOSITORIES: GEO

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

Project description: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.

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

Project description:Most organs have tissue resident immune cells that function during tissue development, homeostasis and disease. Human organoids, derived either from adult tissues or from pluripotent stem cells (PSCs), have been lacking these immune cells, which limits their utility to model many normal and disease processes. Here we describe that human PSC-derived colonic organoids (HCOs) co-develop a diverse population of immune cells. Comparisons to the developing human hematopoietic cells, demonstrate that HCO cultures developed hemogenic endothelium and erythromyeloid progenitors that undergo stereotypical steps in differentiation, resulting in the generation of macrophages. HCO macrophages acquired a transcriptional signature most similar to human fetal small and large intestine tissue-resident macrophages. Functional analyses demonstrate that HCO-macrophages modulate cytokine secretion in response to pro- and anti-inflammatory signals. In addition, macrophages were able to phagocytose and mount a robust response to pathogenic bacteria. In HCOs that were transplanted into mice, macrophages expanded 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 support the conclusion that hemogenic endothelium in HCOs gives rise to multipotent hematopoietic progenitors and functional tissue-resident macrophages.

2023-10-31 | GSE240358 | GEO

Development of functional resident macrophages in human pluripotent stem cell-derived colonic organoids and human fetal colon [bulk rna-seq]

2023-10-31 | GSE240356 | GEO

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

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

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

Project description:Development of functional resident macrophages in human pluripotent stem cell-derived colonic organoids and human fetal colon [scrna-seq]

| PRJNA1003439 | ENA

Development of functional resident macrophages in human pluripotent stem cell-derived colonic organoids and human fetal colon [bulk rna-seq]

Project description:Development of functional resident macrophages in human pluripotent stem cell-derived colonic organoids and human fetal colon [bulk rna-seq]

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Development and Functional Characterization of Fetal Lung Organoids.

Project description:Preterm infants frequently suffer from pulmonary complications due to a physiological and structural lung immaturity resulting in significant morbidity and mortality. Novel in vitro and in vivo models are required to study the underlying mechanisms of late lung maturation and to facilitate the development of new therapeutic strategies. Organoids recapitulate essential aspects of structural organization and possibly organ function, and can be used to model developmental and disease processes. We aimed at generating fetal lung organoids (LOs) and to functionally characterize this in vitro model in comparison to primary lung epithelial cells and lung explants ex vivo. LOs were generated with alveolar and endothelial cells from fetal rat lung tissue, using a Matrigel-gradient and air-liquid-interface culture conditions. Immunocytochemical analysis showed that the LOs consisted of polarized epithelial cell adhesion molecule (EpCAM)-positive cells with the apical membrane compartment facing the organoid lumen. Expression of the alveolar type 2 cell marker, RT2-70, and the Club cell marker, CC-10, were observed. Na+ transporter and surfactant protein mRNA expression were detected in the LOs. First time patch clamp analyses demonstrated the presence of several ion channels with specific electrophysiological properties, comparable to vital lung slices. Furthermore, the responsiveness of LOs to glucocorticoids was demonstrated. Finally, maturation of LOs induced by mesenchymal stem cells confirmed the convenience of the model to test and establish novel therapeutic strategies. The results showed that fetal LOs replicate key biological lung functions essential for lung maturation and therefore constitute a suitable in vitro model system to study lung development and related diseases.

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Project description: Not available

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Human Induced Pluripotent Stem Cell-Derived Macrophages Share Ontogeny with MYB-Independent Tissue-Resident Macrophages.

Project description:Tissue-resident macrophages, such as microglia, Kupffer cells, and Langerhans cells, derive from Myb-independent yolk sac (YS) progenitors generated before the emergence of hematopoietic stem cells (HSCs). Myb-independent YS-derived resident macrophages self-renew locally, independently of circulating monocytes and HSCs. In contrast, adult blood monocytes, as well as infiltrating, gut, and dermal macrophages, derive from Myb-dependent HSCs. These findings are derived from the mouse, using gene knockouts and lineage tracing, but their applicability to human development has not been formally demonstrated. Here, we use human induced pluripotent stem cells (iPSCs) as a tool to model human hematopoietic development. By using a CRISPR-Cas9 knockout strategy, we show that human iPSC-derived monocytes/macrophages develop in an MYB-independent, RUNX1-, and SPI1 (PU.1)-dependent fashion. This result makes human iPSC-derived macrophages developmentally related to and a good model for MYB-independent tissue-resident macrophages, such as alveolar and kidney macrophages, microglia, Kupffer cells, and Langerhans cells.

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Differentiation of Human Pluripotent Stem Cells into Colonic Organoids via Transient Activation of BMP Signaling.

Project description:Gastric and small intestinal organoids differentiated from human pluripotent stem cells (hPSCs) have revolutionized the study of gastrointestinal development and disease. Distal gut tissues such as cecum and colon, however, have proved considerably more challenging to derive in vitro. Here we report the differentiation of human colonic organoids (HCOs) from hPSCs. We found that BMP signaling is required to establish a posterior SATB2+ domain in developing and postnatal intestinal epithelium. Brief activation of BMP signaling is sufficient to activate a posterior HOX code and direct hPSC-derived gut tube cultures into HCOs. In vitro, HCOs express colonic markers and contained colon-specific cell populations. Following transplantation into mice, HCOs undergo morphogenesis and maturation to form tissue that exhibits molecular, cellular, and morphologic properties of human colon. Together these data show BMP-dependent patterning of human hindgut into HCOs, which will be valuable for studying diseases including colitis and colon cancer.

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