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Small sized mesenchymal stem-cells primed with hypoxia attenuate graft-versus-host disease [transcriptome dataset]

ABSTRACT: Mesenchymal stem-cells (MSCs) are of particular interest for treating immune-related diseases due to their immunosuppressive capacities. Here, we show that Small sized MSCs primed with Hypoxia and Calcium ion (SHC-MSCs) exhibit the enhanced functions regarding stemness and immunomodulation for treating allogeneic conflicts. Compared with naïve cultured human umbilical cord-blood MSCs, SHC-MSCs were resistant to the passage dependent cellular senescence mediated by MCP-1 and p53/p21 cascade and highly secreted the pro-angiogenic and immune-modulatory factors, resulting in suppression of T-cell proliferation. Genome-wide DNA methylome and transcriptome analysis indicate that SHC-MSCs characteristically up-regulated immune-modulation, cell adhesion and cell-cycle related genes. As downstream factors, PLK1, ZNF143, DHRS3, and FOG2 proteins played a key role on the beneficial effects of SHC-MSCs, evidenced by the promoted self-renewal, migration, pro-angiogenic, anti-inflammatory, and T cell suppression capacities in their-over-expressing MSCs. Importantly, administration of SHC-MSCs or PLK1-over-expressing cells (PLK1-MSCs) significantly reduced the symptoms of graft-versus-host disease (GVHD) in a humanized mouse model which led to significantly improved survival, less weight loss, and less histopathologic injuries of GVHD target organs compared with naive MSC-infused mice. Collectively, our study suggests that small-sized MSCs primed with hypoxia could advance the therapeutic strategy for the clinical treatment of allogeneic conflicts including GVHD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE108563 | GEO | 2018/08/01

REPOSITORIES: GEO

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Small sized mesenchymal stem-cells primed with hypoxia attenuate graft-versus-host disease [DNA methylome dataset]

Project description:Mesenchymal stem-cells (MSCs) are of particular interest for treating immune-related diseases due to their immunosuppressive capacities. Here, we show that Small sized MSCs primed with Hypoxia and Calcium ion (SHC-MSCs) exhibit the enhanced functions regarding stemness and immunomodulation for treating allogeneic conflicts. Compared with naïve cultured human umbilical cord-blood MSCs, SHC-MSCs were resistant to the passage dependent cellular senescence mediated by MCP-1 and p53/p21 cascade and highly secreted the pro-angiogenic and immune-modulatory factors, resulting in suppression of T-cell proliferation. Genome-wide DNA methylome and transcriptome analysis indicate that SHC-MSCs characteristically up-regulated immune-modulation, cell adhesion and cell-cycle related genes. As downstream factors, PLK1, ZNF143, DHRS3, and FOG2 proteins played a key role on the beneficial effects of SHC-MSCs, evidenced by the promoted self-renewal, migration, pro-angiogenic, anti-inflammatory, and T cell suppression capacities in their-over-expressing MSCs. Importantly, administration of SHC-MSCs or PLK1-over-expressing cells (PLK1-MSCs) significantly reduced the symptoms of graft-versus-host disease (GVHD) in a humanized mouse model which led to significantly improved survival, less weight loss, and less histopathologic injuries of GVHD target organs compared with naive MSC-infused mice. Collectively, our study suggests that small-sized MSCs primed with hypoxia could advance the therapeutic strategy for the clinical treatment of allogeneic conflicts including GVHD.

2018-08-01 | GSE108562 | GEO

Glutathione dynamics determines therapeutic efficacy of mesenchymal stem cells for graft-versus-host disease through CREB1-NRF2 pathway

Project description:Molecular and functional significance of CREB1-NRF2 pathway on GSH dynamics of MSCs which critically determines therapeutic outcomes for treating allogeneic conflicts, including GvHD. A simple and reliable method to real-time monitor the redox status of MSCs which precisely predict their core functions including self-renewal, migration, and immunomodulatory capacities.

2020-06-04 | GSE135998 | GEO

Improved Efficacy of MSCs stably expressing CXCR4 and IL-10 in a xenogeneic Graft versus Host Disease Mouse Model

Project description:Previous clinical trials have shown that mesenchymal stromal cells (MSCs) can modulate graft versus host disease (GvHD) after allogeneic hematopoietic transplantation, although with variable efficacy. To improve the anti-GvHD effect of these cells, adipose tissue derived-human MSCs (Ad-MSCs) were transduced with a lentiviral vector conferring stable expression of CXCR4, a molecule involved in cell migration to inflamed sites, and IL-10, a cytokine with potent anti-inflammatory properties. In vitro experiments showed that the expression of these molecules in Ad-MSCs (named CXCR4-IL10-MSCs) efficiently enhanced their migration towards SDF‐1α and also improved their immunomodulatory properties compared to unmodified Ad‐MSCs (WT‐MSCs). Moreover, using a humanized GvHD mouse model, CXCR4-IL10-MSCs showed improved therapeutic effects, which were confirmed by histopathologic analysis in the target organs. Additionally, compared to WT-MSCs, CXCR4-IL10-MSCs induced a more marked reduction in the number of pro-inflammatory Th1 and Th17 cells, a higher polarization towards an anti-inflammatory T cell profile (CD3+-IL10+ cells), and increased the number of regulatory T and B cells. Our in vitro and in vivo studies strongly suggest that CXCR4-IL10-MSCs should constitute an important new generation of MSCs for the treatment of GvHD in patients transplanted with allogeneic hematopoietic grafts.

2023-01-25 | GSE223390 | GEO

Acute graft-versus-host disease (gene expression profiling)

Project description:Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for high-risk hematological malignancies, yet a major complication associated with this therapy is acute graft-versus-host disease (GVHD). Despite a well-defined pathophysiological mechanism, there are no definitive markers for predicting acute GVHD development or progression to advanced stages. In the current study, we enrolled four acute GVHD and four acute GVHD-free recipients of allogeneic HSCT and collected peripheral blood just prior to onset of clinical acute GVHD for analysis on Affymetrix GeneChip Human Genome U133 Plus 2.0 microarrays. We noted significant differences in expression of 1,658 genes between control and acute GVHD patients, based on an analysis of covariance (ANCOVA) by type of transplant, a pooled error estimate, and a false discovery rate (FDR) of 10%. In conclusion, we offer the first report of a preliminary molecular signature of acute GVHD in allogeneic HSCT patients.

2008-04-09 | GSE7510 | GEO

FK506 and Lactobacillus acidophilus Ameliorate Acute Graft-Versus-Host Disease by Modulating the T Helper 17/Regulatory T-Cell Balance

Project description:Graft-versus-host disease (GvHD) is critical complication after allogeneic hematopoietic stem cell transplantation (HSCT). The immunosuppressants given to patients undergoing allogeneic HSCT disturb the microbiome and the host immune system, potentially leading to dysbiosis and inflammation. The intestinal microbiome is a target for the development of novel therapies for GvHD. We determined the effect of the combination of tacrolimus (FK506) and Lactobacillus acidophilus on GvHD.

2021-05-11 | GSE174214 | GEO

Generation of Allogeneic Hematopoietic Stem Cell-Engineered Invariant Natural Killer T cells for Off-the-Shelf Immunotherapy [VDJ-seq]

Project description:While T cell-based immunotherapies have shown promising clinical responses, current cancer treatments are restricted to autologous cellular products due to the risk of graft-versus-host disease (GvHD) by allogeneic cell transfer. Invariant natural killer T (iNKT) cells are ideal cell carriers for developing off-the-shelf allogeneic cellular therapy because they are powerful immune cells targeting a broad range of cancers without causing GvHD. However, current immunotherapies using iNKT cells are impeded by their extremely low number in cancer patients. In this study, we aimed to overcome this limitation by generating a large number of iNKT cells through TCR engineering of human hematopoietic stem cells (HSCs) and differentiation of HSCs to iNKT cells in an in vitro cultured system. Additionally, Chimeric antigen receptor (CAR) engineering and the CRISPR-Cas9 gene editing tool were utilized to enhance the tumor killing efficacy of iNKT cells and eliminate HLA molecules on their surface, making the cellular product suitable for cancer therapy and allogeneic adoptive transfer. Our results demonstrated successful generation of the promising off-the-shelf B cell maturation antigen (BCMA)-CAR engineered iNKT cells for treating multiple myeloma, and the same strategy will be applied to multiple cellular products for treating other cancers.

2021-12-01 | GSE164500 | GEO

Generation of Allogeneic Hematopoietic Stem Cell-Engineered Invariant Natural Killer T cells for Off-the-Shelf Immunotherapy [RNA-seq]

2021-12-01 | GSE164425 | GEO

Single-cell RNA sequencing analysis of blood B cells from human allogeneic hematopoietic transplant patients

Project description:Single cell analysis of gene expression in blood B cells from allogeneic hematopoietic stem cell transpant (HCT) patients that either developed chronic GVHD, or never developed chronic GVHD.

2023-05-02 | GSE161343 | GEO

Syngeneic, in contrast to allogeneic, mesenchymal stem cells have superior therapeutic potential following spinal cord injury

Project description:We evaluated the importance of histocompatibility of transplanted MSCs in terms of therapeutic potential. Mouse syngeneic MSCs or allogeneic MSCs were transplanted following SCI in mouse. In this study we found that syngeneic, but not allogeneic, MSCs alternatively activated macrophages resulting in a down-regulation of pro-inflammation. Syngeneic MSCs also had a general suppressive effect on the immune response as compared to allogeneic MSCs. Additionally, syngeneic, but not allogeneic, MSCs significantly enhanced the recovery of hind limb function. In this study we show that the histocompatibility of transplanted MSCs is of importance for their therapeutic potential.

2019-10-23 | GSE139227 | GEO

Single cell RNA sequencing of mouse donor T cells after graft-versus-host disease (GVHD) model

Project description:Lethally irradiated mice were transferred with bone marrow cells together with allogeneic Treg cells isolated from CD226+/+ TIGIT+/+, CD226-/- TIGIT+/+, CD226+/+ TIGIT-/-, or CD226-/- TIGIT-/- mice, followed by allogeneic wild-type Tconv cells two days later to induce acute GVHD. We performed scRNA sequencing of donor T cells isolated from the spleen of recipient mice eight days after GVHD induction.

2021-05-18 | GSE155250 | GEO

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