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DLL4 and VCAM1 enhance the emergence of T cell-competent hematopoietic progenitors from human pluripotent stem cells

ABSTRACT: T cells show tremendous efficacy as cellular therapeutics. However, obtaining primary T cells from human donors is expensive and variable. Pluripotent stem cells (PSCs) have the potential to provide a renewable source of T cells, but differentiating PSCs into hematopoietic progenitors with T cell potential remains a significant challenge. Here, we report an efficient serum- and feeder-free system for differentiating human PSCs into hematopoietic progenitors and T cells. This fully-defined approach allowed us to study the impact of individual proteins on blood emergence and differentiation. Providing DLL4 and VCAM1 during the endothelial-to-hematopoietic transition enhanced downstream progenitor T cell output by ~80-fold. These two proteins synergised to activate notch signalling in nascent hematopoietic stem and progenitor cells and VCAM1 additionally promoted an inflammatory transcriptional program. We also established optimised media formulations that enabled efficient and chemically defined maturation of functional CD8αβ+, CD4-, CD3+, TCRαβ+ T cells with a diverse TCR repertoire.

ORGANISM(S): Homo sapiens

PROVIDER: GSE207157 | GEO | 2022/07/02

REPOSITORIES: GEO

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Organoid-induced differentiation of conventional T cells from human pluripotent stem cells

Project description:Generation of T cells from pluripotent stem cells (PSC) has the potential to transform adoptive immunotherapy for cancer into universal donor, off-the-shelf cellular therapies. However, differentiation of human PSCs into fully mature T cells has been challenging with existing methods. We report that a 3D organoid method permitted efficient differentiation of human embryonic stem cell and induced pluripotent stem cell-derived mesoderm progenitors to mature, functional conventional T cells with a diverse T cell receptor (TCR) repertoire. This continuous culture system supported both hematopoietic induction and terminal differentiation to naïve, conventional CD3+CD8αβ+ and CD3+CD4+ T cells. Introduction of a Class I-restricted TCR in PSCs produced antigen-specific CD8αβ+ T cells lacking endogenous TCR expression. Functional assays and RNA sequencing aligned PSC-derived T cells with primary naïve conventional CD8+ T cells. The organoid system presented here provides an effective and scalable platform to generate functional mature T cells from human PSCs.

2019-08-20 | GSE116015 | GEO

DLL4 and VCAM1 enhance the emergence of T cell-competent hematopoietic progenitors from human pluripotent stem cells

Project description:DLL4 and VCAM1 enhance the emergence of T cell-competent hematopoietic progenitors from human pluripotent stem cells

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RNA-seq of VCAM1-positive cardiac fibroblasts (VCF) and VCAM1-negative cardiac fibroblasts (VNCF).

Project description:This experiment aims at comparing the transcriptomic profiles of two subpopulations of fetal human cardiac fibroblasts (HCF) defined by their relative expression of VCAM1. VCAM1-positive and VCAM1-negative populations were isolated from commercial fetal HCF by MACS against VCAM1. The RNA-seq procedure was outsourced to GENEWIZ (South Plainfield, NJ, USA), and subsequent analysis was performed in-house. Briefly, total mRNA was captured using the NEBNext Poly(A) mRNA Magnetic Isolation Module, and the library was constructed with the NEBNext Ultra RNA Library Prep Kit for Illumina. Sequencing was realized on an Illumina HiSeq 2500 System.

2020-08-08 | E-MTAB-9161 | biostudies-arrayexpress

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Gene expression profile of DLL4+ and DLL4- Hemato-Endothelial Progenitors (HEPs) subpopulations

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The VCAM1–ApoE pathway directs microglial chemotaxis and alleviates Alzheimer’s disease pathology

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2023-07-18 | GSE208006 | GEO

Spatiotemporal Regulation of Cholangiocarcinoma Growth and Dissemination by Peritumoral Myofibroblasts in a Vcam1-dependent Manner

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2023-02-22 | GSE223562 | GEO

RNA-seq of VCAM1-positive cardiac fibroblasts (VCF) and VCAM1-negative cardiac fibroblasts (VNCF).

Project description:RNA-seq of VCAM1-positive cardiac fibroblasts (VCF) and VCAM1-negative cardiac fibroblasts (VNCF).

| PRJEB38639 | ENA

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Identification of chondrocyte subsets during human development

Project description:Joint injury and osteoarthritis affect millions of people worldwide, but attempts to generate articular cartilage using adult stem/progenitor cells have been unsuccessful. We hypothesized that recapitulation of the human developmental chondrogenic program using pluripotent stem cells (PSCs) may represent a superior approach for cartilage restoration. Using laser capture microdissection followed by microarray analysis, we first defined a surface phenotype (CD146low/negCD166low/negCD73+CD44lowBMPR1B+) distinguishing the earliest cartilage committed cells (pre-chondrocytes) at 5-6 weeks of development; pellet assays confirmed these cells as functional, chondrocyte-restricted progenitors. Flow cytometry, qPCR and immunohistochemistry at 17 weeks revealed that the superficial layer of peri-articular chondrocytes was enriched in cells with this surface phenotype. Isolation of cells with a similar immunophenotype from differentiating human PSCs revealed a population of CD166negBMPR1B+ putative pre-chondrocytes. Functional characterization confirmed these cells as cartilage-committed, chondrocyte progenitors. The identification of a specific molecular signature for primary cartilagecommitted progenitors may provide essential knowledge for the generation of purified, clinically relevant cartilage cells from PSCs. A total of 15 samples were analyzed. In the first comparison, there were 6 biological replicates for both the chondrogenic condensations and total limb cells. In the second comparison, three biological replicates of chondrocytes from the articular region were compared to the 6 replicates of the condensations.

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