scispace - formally typeset
Search or ask a question
Author

Joshua H. Wu

Bio: Joshua H. Wu is an academic researcher from University of Michigan. The author has contributed to research in topics: Stem cell & Population. The author has an hindex of 6, co-authored 9 publications receiving 92 citations.

Papers
More filters
Journal ArticleDOI
TL;DR: This work uses single-cell mRNA sequencing with in situ validation approaches to interrogate human intestinal development from 7-21 weeks post conception, assigning molecular identities and spatial locations to cells and factors that comprise the niche.

83 citations

Journal ArticleDOI
TL;DR: HIOs can co-differentiate a native EC population that is properly patterned with an intestine-specific EC transcriptional signature in vitro, and it is found that HIO ECs grown in vitro share the highest similarity with native intestinal ECs relative to kidney and lung.

69 citations

Journal ArticleDOI
10 Jun 2021-Cell
TL;DR: This work generates a single-cell transcriptome atlas from multiple developing endodermal organs of the respiratory and gastrointestinal tract and implements the atlas as a high-dimensional search space to benchmark human pluripotent stem cell (hPSC)-derived intestinal organoids (HIOs) under multiple culture conditions.

53 citations

Posted ContentDOI
15 Mar 2020-bioRxiv
TL;DR: HIOs can co-differentiate a native EC population that are properly patterned with an intestine-specific EC transcriptional signature in vitro, and are shown to share the highest similarity with native intestinal ECs relative to kidney and lung.
Abstract: SUMMARY Human pluripotent stem cell (hPSC)-derived intestinal organoids (HIOs) generated using directed differentiation lack some cellular populations found in the native organ, including vasculature. Using single cell RNA sequencing (scRNAseq), we have identified a transient population of endothelial cells (ECs) present early in HIO differentiation that are lost over time in culture. Here, we have developed a method to enhance co-differentiation and maintenance of ECs within HIOs (vHIOs). Given that ECs are known to possess organ specific gene expression, morphology and function, we used bulk RNAseq and scRNAseq to interrogate the developing human intestine, lung, and kidney in order to identify organ-enriched EC-gene signatures in these organ systems. By comparing organ-specific gene signatures along with markers validated by fluorescent in situ hybridization to HIO ECs, we find that HIO ECs grown in vitro share the highest similarity with native intestinal ECs relative to kidney and lung. Together, these data show that HIOs can co-differentiate a native EC population that are properly patterned with an intestine-specific EC transcriptional signature in vitro.

37 citations

Posted ContentDOI
06 Apr 2021-bioRxiv
TL;DR: In this article, single cell RNA sequencing data from multiple human lung specimens and identified a mesenchymal cell population present during development that is highly enriched for expression of the WNT agonist R-SPONDIN2 (RSPO2), and adjacent epithelial bud tip progenitors are enriched for the RSPO 2 receptor LGR5.
Abstract: SUMMARY Mammalian respiratory system development is regulated by complex reciprocal signaling events that take place between epithelial cells and the surrounding mesenchymal cells; however, mesenchymal heterogeneity and function in the developing human lung is poorly understood. We interrogated single cell RNA sequencing data from multiple human lung specimens and identified a mesenchymal cell population present during development that is highly enriched for expression of the WNT agonist R-SPONDIN2 (RSPO2), and we found that adjacent epithelial bud tip progenitors are enriched for the RSPO2 receptor LGR5. By carrying out functional experiments using organoid models, lung explant cultures, and FACS-isolated RSPO2+ mesenchyme, we show that RSPO2 is a critical niche cue that potentiates WNT signaling in human lung progenitors to maintain their multipotency.

17 citations


Cited by
More filters
Journal ArticleDOI
04 Feb 2021-Cell
TL;DR: In this paper, single-cell RNA sequencing and spatial transcriptomics were used to characterize intestinal morphogenesis through time and identify 101 cell states including epithelial and mesenchymal progenitor populations and programs linked to key morphogenetic milestones.

189 citations

Journal ArticleDOI
09 Sep 2021-Nature
TL;DR: The cellular landscape of the human intestinal tract is dynamic throughout life, developing in utero and changing in response to functional requirements and environmental exposures as discussed by the authors, using single-cell RNA sequencing and antigen receptor analysis of almost half a million cells from up to 5 anatomical regions of the developing and up to 11 distinct anatomical regions in the healthy human gut.
Abstract: The cellular landscape of the human intestinal tract is dynamic throughout life, developing in utero and changing in response to functional requirements and environmental exposures. Here, to comprehensively map cell lineages, we use single-cell RNA sequencing and antigen receptor analysis of almost half a million cells from up to 5 anatomical regions in the developing and up to 11 distinct anatomical regions in the healthy paediatric and adult human gut. This reveals the existence of transcriptionally distinct BEST4 epithelial cells throughout the human intestinal tract. Furthermore, we implicate IgG sensing as a function of intestinal tuft cells. We describe neural cell populations in the developing enteric nervous system, and predict cell-type-specific expression of genes associated with Hirschsprung’s disease. Finally, using a systems approach, we identify key cell players that drive the formation of secondary lymphoid tissue in early human development. We show that these programs are adopted in inflammatory bowel disease to recruit and retain immune cells at the site of inflammation. This catalogue of intestinal cells will provide new insights into cellular programs in development, homeostasis and disease. Cells from embryonic, fetal, paediatric and adult human intestinal tissue are analysed at different locations along the intestinal tract to construct a single-cell atlas of the developing and adult human intestinal tract, encompassing all cell lineages.

163 citations

Journal ArticleDOI
TL;DR: An in-depth single-cell map of the developing human intestine at 6–10 weeks post-conception is generated, revealing the transcriptional profile of cycling epithelial precursor cells; distinct from LGR5-expressing cells.

135 citations

Journal ArticleDOI
13 May 2021-Nature
TL;DR: The Human Developmental Cell Atlas (HDCA) project as discussed by the authors aims to create a comprehensive reference map of cells during development by mapping and modelling human development using state-of-the-art technologies.
Abstract: The Human Developmental Cell Atlas (HDCA) initiative, which is part of the Human Cell Atlas, aims to create a comprehensive reference map of cells during development. This will be critical to understanding normal organogenesis, the effect of mutations, environmental factors and infectious agents on human development, congenital and childhood disorders, and the cellular basis of ageing, cancer and regenerative medicine. Here we outline the HDCA initiative and the challenges of mapping and modelling human development using state-of-the-art technologies to create a reference atlas across gestation. Similar to the Human Genome Project, the HDCA will integrate the output from a growing community of scientists who are mapping human development into a unified atlas. We describe the early milestones that have been achieved and the use of human stem-cell-derived cultures, organoids and animal models to inform the HDCA, especially for prenatal tissues that are hard to acquire. Finally, we provide a roadmap towards a complete atlas of human development. This Perspective outlines the Human Developmental Cell Atlas initiative, which uses state-of-the-art technologies to map and model human development across gestation, and discusses the early milestones that have been achieved.

83 citations

Journal ArticleDOI
TL;DR: PSC-HIOs are a valuable tool to study SARS-CoV-2 infection and to identify and validate drugs especially with potential action in the gut to understand and validate drug efficiency in COVID-19 patients.
Abstract: Background and aims The COVID-19 pandemic has spread worldwide and poses a severe health risk. While most patients present mild symptoms, descending pneumonia can lead to severe respiratory insufficiency. Up to 50% of patients show gastrointestinal symptoms like diarrhea or nausea, intriguingly associating with prolonged symptoms and increased severity. Thus, models to understand and validate drug efficiency in the gut of COVID-19 patients are of urgent need. Methods Human intestinal organoids derived from pluripotent stem cells (PSC-HIOs) have led, due to their complexity in mimicking human intestinal architecture, to an unprecedented number of successful disease models including gastrointestinal infections. Here, we employed PSC-HIOs to dissect SARS-CoV-2 pathogenesis and its inhibition by remdesivir, one of the leading drugs investigated for treatment of COVID-19. Results Immunostaining for viral entry receptor ACE2 and SARS-CoV-2 spike protein priming protease TMPRSS2 showed broad expression in the gastrointestinal tract with highest levels in the intestine, the latter faithfully recapitulated by PSC-HIOs. Organoids could be readily infected with SARS-CoV-2 followed by viral spread across entire PSC-HIOs, subsequently leading to organoid deterioration. However, SARS-CoV-2 spared goblet cells lacking ACE2 expression. Importantly, we challenged PSC-HIOs for drug testing capacity. Specifically, remdesivir effectively inhibited SARS-CoV-2 infection dose-dependently at low micromolar concentration and rescued PSC-HIO morphology. Conclusions Thus, PSC-HIOs are a valuable tool to study SARS-CoV-2 infection and to identify and validate drugs especially with potential action in the gut.

72 citations