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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE240358 | 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 [bulk rna-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 | GSE240356 | GEO

Development of human brain organoids with functional vascular-like system

Project description:Human cortical organoids (hCOs), derived from human embryonic stem cells (hESCs), provide an excellent platform to study human brain development and diseases in complex 3D tissue. However, current hCOs lack microvasculature, resulting in limited oxygen and nutrient delivery to inner-most parts of hCOs. Previous studies demonstrated that the expression of human ETS variant 2 (hETV2) directly converts human fibroblasts to functional endothelial cells. Here, we engineered hESCs to ectopically express hETV2 to create in vitro vasculature in hCOs, namely vhCOs (vascularized hCOs). hETV2-expressing cells in hCOs contributed to forming a complex vascular network in hCOs. Importantly, the presence of vascularization resulted in enhanced functional maturation of organoids. We found that vhCOs acquired several blood-brain barrier (BBB) characteristics including increased expression of tight junctions, nutrient transporters, and trans-endothelial electrical resistance. Finally, hETV2-induced endothelium supported the formation of perfused blood vessels in vivo. These vhCOs form vasculature that resemble early prenatal brain, and present a robust model to study brain disease in vitro.

2019-09-19 | GSE134049 | GEO

Human cardiac organoids to model COVID‐19 cytokine storm induced cardiac injuries

Project description:Acute cardiac injuries occur in 20%–25% of hospitalized COVID‐19 patients. Herein, we demonstrate that human cardiac organoids (hCOs) are a viable platform to model the cardiac injuries caused by COVID‐19 hyperinflammation. As IL‐1β is an upstream cytokine and a core COVID‐19 signature cytokine, it was used to stimulate hCOs to induce the release of a milieu of proinflammatory cytokines that mirror the profile of COVID‐19 cytokine storm. The IL‐1β treated hCOs recapitulated transcriptomic, structural, and functional signatures of COVID‐19 hearts. The comparison of IL‐1β treated hCOs with cardiac tissue from COVID‐19 autopsies illustrated the critical roles of hyper‐inflammation in COVID‐19 cardiac insults and indicated the cardioprotective effects of endothelium. The IL‐1β treated hCOs thus provide a defined and robust model to assess the efficacy and potential side effects of immunomodulatory drugs, as well as the reversibility of COVID‐19 cardiac in- juries at baseline and simulated exercise conditions.

2023-12-20 | GSE250520 | GEO

Multicellular human cardiac organoids transcriptomically model distinct tissue-level features of adult myocardium

Project description:Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been widely used for disease modeling and drug cardiotoxicity screening. To this end, we recently developed human cardiac organoids (hCOs) for modeling human myocardium. Here, we perform a transcriptomic analysis of various in vitro hiPSC-CM platforms (2D iPSC-CM, 3D iPSC-CM and hCOs) to deduce strengths and limitations of these in vitro models. We further compared iPSC-CM models to human myocardium samples. Our data shows that the 3D in vitro environment of 3D hiPSC-CMs and hCOs stimulates expression of genes associated with tissue formation. hCOs demonstrated diverse physiologically relevant cellular functions compared to hiPSC-CM only models. Including other cardiac cell types within hCOs led to more transcriptomic similarly to adult myocardium. hCOs lack matured cardiomyocytes and immune cells which limits a complete replication of human adult myocardium. In conclusion, 3D hCOs are transcriptomically similar to myocardium, and future developments of engineered 3D cardiac models would benefit from diversifying cell populations, especially immune cells.

2021-08-31 | GSE181397 | GEO

Transcriptional profiling of Tissues, Tumors, and associated cells in mice with gene mutations relevant to colorectal cancer and macrophage infiltration

Project description:A profile of gene expression differences in mouse colon tissue, colonic tumors, organoids from colon tumors and colonic macrophages with genetic changes and drug treatment.

2023-06-13 | GSE234501 | GEO

Effects of early geometric confinement on the transcriptomic profile of human cerebral organoids

Project description:Here, we used agarose microwells to control embryos body (EB) shapes and generated whole brain human cerebral organoids (hCO) from these EBs to investigate the effects of early spatial regulation on transcriptomic changes during brain region specification using bulk RNA sequencing. Our results showed that gross morphological and transcriptional changes related to hCO differentiation were similar between 96-well and microwell hCOs, indicating that the microwell growth environment did not significantly affect the overall neural differentiation or viability of the hCOs. However, investigating individual developmental time points and comparing across 96-well and microwell conditions more closely revealed notable differences in genes associated with pluripotency, mesoderm, MGE, retina and cortical development, and epithelial and mesenchymal fates, implying that the microwell growth environment may bias lineage commitment in neurodevelopment. Furthermore, we found that the direction and intensity of this transcriptional bias was associated with the starting EB shapes. The butterfly shape showed the most noticeable differences, followed closely by the peanut shape. Among other notable differences, round microwells exhibited a potential delay in the kinetics of neurodevelopment, and our results also demonstrated that non-spherical shapes may favor the development of MGE-associated brain regions and cell types over cortical regions.

2021-02-23 | GSE167208 | GEO

Generation of anti-GD2 CAR macrophages from human pluripotent stem cells for cancer immunotherapies

Project description:We generate macrophages from pluripotent stem cells (PSCs) with GD2 CARs integrated into AAVS1 locus. To produce CAR macrophages (CAR-M) we established a serum- and feeder-free differentiation protocol which generates macrophages through arterialized hemogenic endothelium.

2022-12-31 | GSE201174 | GEO

Patient-derived iPSC-cerebral organoid modeling of the 17q11.2 microdeletion syndrome establishes CRLF3 as a critical regulator of neurogenesis

Project description:Neurodevelopmental disorders are often caused by chromosomal microdeletions encompassing numerous contiguous genes. One such microdeletion on chromosome 17q11.2, involving the NF1 gene and flanking regions ( NF1 total gene deletion; NF1 -TGD), occurs in a subset of Neurofibromatosis type 1 (NF1) patients with severe developmental delays and intellectual disability. Using patient-derived human induced pluripotent stem cell (hiPSC)-cerebral organoids (hCOs), we identified both neural stem cell (NSC) proliferation and neuronal maturation abnormalities in NF1 -TGD hCOs. While increased NSC proliferation resulted from decreased NF1 /RAS regulation, the neuronal defects (delayed neuronal differentiation, increased immature neuron apoptosis, and impaired dendrite maturation) were caused by reduced cytokine receptor-like factor 3 ( CRLF3 ) expression. Furthermore, we demonstrated a higher autistic trait burden in NF1 patients harboring a deleterious germline mutation in the CRLF3 gene (c.1166T>C, p.Leu389Pro). Collectively, these findings identify a new causative gene within the NF1 -TGD locus responsible for hCO neuronal abnormalities and autism in children with NF1.

2021-06-07 | GSE166080 | GEO

Probing Hemogenic Precursors with Endoglin Regulatory Elements uncovers LRP2 as a Regulator of Hematopoiesis

Project description:Different combinations of Endoglin tissue specific enhancers define hemangioblast and hemogenic endothelium cell fractions

2016-12-06 | GSE77390 | GEO

Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment [RNA-seq]

Project description:Macrophages are hematopoietic cells critical for innate immune defense, but also control organ homeostasis in a tissue-specific manner. Tissue-resident macrophages, therefore, provide a well-defined model to study the impact of ontogeny and microenvironment on chromatin state. Here, we profile the dynamics of four histone modifications across seven tissue-resident macrophage populations, as well as monocytes and neutrophils. We identify 12,743 macrophage-specific enhancers and establish that tissue-resident macrophages have distinct enhancer landscapes. Our work suggests that a combination of tissue and lineage-specific transcription factors form the regulatory networks controlling chromatin specification in tissue-resident macrophages. The environment has the capacity to alter the chromatin landscape of macrophages derived from transplanted adult bone marrow in vivo and even differentiated macrophages are reprogrammed when transferred into a new tissue. Altogether, these data provide a comprehensive view of macrophage regulation and highlight the importance of microenvironment along with pioneer factors in orchestrating macrophage identity and plasticity. 7 tissue-resident macrophage populations were isolated, as well as monocytes and neutrophils, and transcriptome analysis was performed. Experiment was done in duplicates.

2014-12-05 | E-GEOD-63340 | biostudies-arrayexpress

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