Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

VLA-4 Agonist Promote Engraftment and Cell Immune Reconstitution of Allogeneic Hematopoietic Stem Cells

ABSTRACT: Successful engraftment and early immune reconstitution of donor hematopoietic stem cells (HSCs) are crucial for allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, little is known about how to promote implantation and early immune reconstitution of HSCs through regulating its own functions. Here, we identified very-late antigen (VLA-4) as a pivotal target in regulating HSC implantation. Critically, we screened out a VLA-4 agonist, which could promote the implantation and long-term hematopoietic reconstitution of donor HSCs in a mixed donor chimerism (MDC) mouse model and serial xenotransplantation model of human CD34+ cells from umbilical cord blood (UCB). Competitive transplantation mouse model and limited dilution assay for UCB CD34+ cells revealed that VLA-4 agonist could enhance the self-renewal capacity of HSCs and increase the number of severe combined immunodeficient (SCID)-repopulating cells (SRCs) to five-fold in vivo. Furthermore, the VLA-4 agonist could facilitate early post-transplant cell immune reconstitution by enhancing T cell output of HSCs. VLA-4 agonist regulates HSC functions and lymphoid progenitor differentiation through affecting the ERK1/2 phosphorylation pathway, whereas may not increase the risk of leukemia transformation. These findings indicate that the VLA-4 agonist holds a great clinical translational potential in enhancing engraftment of HSCs and early cellular immune reconstitution following allo-HSCT.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE264056 | GEO | 2026/03/23

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

GVHD-mediated Vicious Cascade: Impaired Reconstitution of Immunosuppressive Donor Plasmacytoid Dendritic Cells

Project description:In patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), severe graft-versus-host disease (GVHD) is tied to failed donor plasmacytoid DC (pDC) reconstitution. The mechanism whereby GVHD causes donor pDC defects and the precise role donor pDCs play in GVHD remain poorly understood. pDCs develop from HSCs in successive stages through Flt3 signaling-dependent differentiation, beginning as multi-potent progenitors (MPPs) and later becoming common DC progenitors. We observed that MPPs were critical for sustaining pDCs and were severely depleted during GVHD. Loss of MPPs was associated with decreased amounts of MPP-producing HSCs and mTOR activation-induced cell death of proliferating MPPs. Additionally, GM-CSF derived from alloreactive T cells subverted MPP production of pDCs. Together, GVHD and alloreactive T cells caused donor pDC defects by impairing the generation, maintenance and differentiation of HSCs and MPPs. Importantly, pDCs suppressed the proliferation and expansion of activated autologous CD4+ T cells via a type I-IFN signaling-dependent mechanism. Transfer of donor pDCs early after transplantation repressed GVHD and preserved potent GVL effects, significantly improving the survival of leukemia mice undergoing allo-HSCT. Our findings identify novel strategies that improve the recovery of donor pDCs early after allo-HSCT and thus may represent an effective therapy to control GVHD. Our findings have broad implications for other diseases in which functional DC development is impaired, such as chronic infections, autoimmunity and cancer.

2021-01-06 | GSE143788 | GEO

Single or Double Donor Umbilical Cord Blood Transplant in Treating Patients With High-Risk Hematologic Malignancies

Project description:This study will determine the safety and applicability of experimental forms of umbilical cord blood (UCB) transplantation for patients with high risk hematologic malignancies who might benefit from a hematopoietic stem cell transplant (HSCT) but who do not have a standard donor option (no available HLA-matched related donor (MRD), HLA-matched unrelated donor (MUD)), or single UCB unit with adequate cell number and HLA-match).

| 2129398 | ecrin-mdr-crc

Transcriptional analysis of beta-catenin overexpressing T cells

Project description:Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the most widely applied forms of adaptive immunotherapy. Both the detrimental graft-versus-host disease (GVHD) and the beneficial graft-versus-leukemia (GVL) effects occurring after allo-HSCT are largely mediated by alloantigen-reactive donor T cells in the graft. Separating GVHD from GVL effects is a formidable challenge, and a greater understanding of donor T cell biology is required to accomplish the uncoupling of GVHD from GVL. Here, we tested a novel mouse model of transgenic over-expression of human β-catenin (Cat-Tg) in an allo-HSCT model. Our data show that T cells from Cat-Tg mice did not cause GVHD. Surprisingly, Cat-Tg T cells maintained the GVL effect. Donor T cells from Cat-Tg mice exhibited significantly lower inflammatory cytokine production and reduced donor T cell proliferation, while upregulating cytotoxic mediators that resulted in enhanced cytotoxicity. RNA sequencing data revealed changes in the expression of 1169 genes for CD4, and 1006 genes for CD8+T cells involved in essential aspects of immune response and GVHD pathophysiology. Transgenic over-expression of human β-catenin primarily affects CD8+ T cell phenotype. Altogether, our data suggest that β-catenin is a druggable target for developing therapeutic strategies to reduce GVHD while preserving the beneficial GVL effects following allo-HSCT treatment

2021-08-01 | GSE180808 | GEO

Multiomic Single Cell Evaluation Reveals Inflammatory Cytokines Affect Innate Lymphoid Cell Fate After Allogeneic Stem Cell Transplantation [ChIP-Seq]

Project description:Type II innate lymphoid cells (ILC2s) maintain homeostasis and barrier integrity in mucosal tissues. Previous work has shown that in mice and humans, ILC2s fail to reconstitute after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Determining the mechanisms involved in their impaired reconstitution could improve transplant outcomes. By integrating chromatin and transcriptomic analysis of marked, transplanted ILC2s at the single cell level, we identify a previously unreported population of converted ILC1-like cells in the small intestine post-transplant. Exposure of ILC2s to proinflammatory cytokines in vitro results in a mixed ILC1-ILC2 phenotype but was able to convert only an extremely small population of ILC2s to ILC1s as observed in vivo. Whereas ILC2s protected against acute graft-versus-host disease (aGVHD) mediated-morbidity and mortality, infusion of proinflammatory cytokine-exposed ILC2s accelerated aGvHD. Finally, circulating peripheral blood mononuclear cells from patients with aGvHD have an altered ILC2-associated chromatin landscape compared to transplanted controls. These data demonstrate, for the first time, that ILC2s fail to repopulate their protective niche after allo-HSCT in part due to conversion to a pro-pathogenic population marked by an ILC1-like chromatin state, providing novel insights into the contribution of ILC plasticity to aGvHD pathogenesis after allo-HSCT.

2023-09-14 | GSE232000 | GEO

Reconstitution of the uterine immune milieu after transplantation (scRNA-seq)

Project description:Maintenance of tissue-specific immunity is important for immunological fitness, but its establishment have been difficult to assess in humans. Here, we investigated reconstitution of the human uterine immune system by studying women undergoing uterus solid organ transplantation (UTx) or hematopoietic stem cell transplantation (HSCT). Through single-cell identification based on SNPs and disparate HLA expression using single-cell RNA sequencing or high-parameter flow cytometry, donor vs recipient cell origin was determined, and features of these cells were studied. Endometrial immune cell reconstitution occurred after both UTx and HSCT, at the transcriptomic, phenotypic, and spatial level. This occurred despite tacrolimus-induced calcineurin-mediated NFAT pathway inhibition, which affected de novo induction of tissue-residency features in vitro. Intriguingly, after HSCT, immune cells of male origin could reconstitute the endometrium. Collectively, our results proved insights into tissue immune system persistence and reconstitution capabilities in an organ undergoing continuous regeneration.

2025-08-22 | GSE255202 | GEO

Recipient and donor expression differences in children treated with HSCT

Project description:Reconstitution of cell lines and occurrence of complications following hematopoietic stem cell transplantation (HSCT) are regulated by genome expression. Microarray technique allows for simultaneous assessment of expression of nearly all human genes. The objective of the study was to compare whole genome expression in children before and after HSCT. A total of 44 children treated with HSCT were enrolled in the study. Gene expression was measured before HSCT (pre-HSCT group; n=44) and after a median of 6 months after allogenic HSCT (post-HSCT group; n=27; all children were included in the pre-HSCT group). Neoplasms were the indication for HSCT in 73% of the patients. Whole genome expression was assessed in leukocytes using GeneChip® HumanGene 1.0 ST microarray. The analysis of genomic profiles before and after HSCT revealed 18 significantly different genes with defined function. These genes are responsible for proliferation and differentiation of cells (14 genes), apoptosis (8 genes), migration of cells (3 genes) and fluid/electrolyte homeostasis (2 genes). Our findings allow us to conclude that activation of genes involved in reconstitution of donor cell lines, and those related to immune reactions observed after HSCT, form the genetic background for physiological and pathological processes following HSCT.

2016-10-19 | GSE88852 | GEO

Faecal Microbiota Transplantation After Allogeneic Stem Cell Transplantation

Project description:The aim of this study is to assess the Fecal Microbiota Transplantation (FMT) efficacy in the prevention of allogeneic hematopoietic stem cell transplantation (allo-HSCT) complications and particularly Graft versus Host Disease (GvHD). The hypothesis of this study is that allogeneic FMT may improve outcomes of these patients.

| 2381286 | ecrin-mdr-crc

Comparative analysis of gene expression by human Umblical Cord (UCB)-CD34+ Hematopoietic Stem Cells (HSCs) and human induced pluripotent stem (iPS) cell-derived CD34+ Hematopoietic Progenitor Cells (HPCs)

Project description:Hematopoietic stem and progenitor cells are a rare, self-renewing bone marrow resident population capable of giving rise to all circulating hematopoietic cells. They can be used therapuetically for reconstituting defective or ablated hematopoietic systems following chemotherapy, and for inducing tolerance toward allografts of the same haplotype as the HSC donor. There are several sources for HSCs, such as the adult bone marrow, or umblical cord blood, which is more replete with such HSCs. However, HSCs obtained from such sources may be immunogenic, especially if isolated from adult bone marrow. To overcome this issue, our lab has establsihed human induced pluripotent stem cell-derived HPCs with the hope of creating a nonimmunogenic, readily available and unlimited source of HSCs to use for therapy. The goal of this study was to compare the gene expression profiles of naturally found HSCs (UCB-CD34+ HSCs) and HPCs differentiated from 4 different human iPS cell lines (iPS-HPCs), so as to determine the variation between the four iPS-HPCs and whether there were any differences between these HPCs and naturally found HSCs. We utilized 4 iPS cells for this study (detailed descriptions are provided below). iPS cells were differentiated into hematopoietic progenitor cells by coculture on OP9 stromal cells, followed by enrichment of CD34+ cells through immunomagnetic bead separation. The UCB-CD34+ cells were isolated from frozen cord samples through immunomagnetic bead separation. Total RNA was isolated and human gene Affymetrix ST 1.0 arrays performed at the University of Iowa DNA core facility. Data was analyzed, normalized and plotted on BRB Array Tools.

2013-10-23 | E-GEOD-46888 | biostudies-arrayexpress

Functional screen for novel regulators of murine hematopoietic stem cell in vivo repopulating activity

Project description:Although Hematopoietic Stem Cell Transplantation (HSCT) routinely treats hematologic disease, many patients experience adverse outcomes. Understanding the molecular regulation of HSC engraftment is paramount to improving HSCT regimens. Here, we executed a large-scale transplant-based functional screen for novel regulators of HSC repopulation.. Of >50 gene candidates tested, 18 were required for in vivo hematopoietic repopulation and two were detrimental to repopulation, as their loss enhanced this activity. Each Hit was validated in a second screen. Eleven Hits have never before been implicated in HSC biology. We further show that one novel Hit, Foxa3, is required for optimal engraftment as Foxa3-/- bone marrow is defective in both primary and secondary hematopoietic reconstitution. We also present evidence that Foxa3 is a novel pioneer factor in HSC. Each gene identified in our screen is a window into the cellular mechanisms that control hematopoietic reconstitution. Thus, this work represents a resource to the community to better understand these processes 3 FOXA3 KO samples are compared to 3 wt samples

2015-07-01 | E-GEOD-63830 | biostudies-arrayexpress

Longitudinal single-cell dynamics in chronic lymphocytic leukemia mirror disease history

Project description:Longitudinally sampled peripheral blood samples of 9 CLL patients were subjected to single cell RNA sequencing before and at relapse after chemotherapy with fludarabine, cyclophosphamide and rituximab (FCR); allogeneic hematopoietic stem cell transplantation (RIC allo-HSCT); ibrutinib treatment, or before and after transformation to Richter's syndrome.

2021-06-09 | GSE165087 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data