Transcriptomic characterization of endogenous and transplanted myeloid cells of the brain
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE255893 | GEO | 2026/07/18
REPOSITORIES: GEO
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Project description:The replacement of microglia with myeloid cells derived from transplanted bone marrow represents a promising cell therapeutic concept for different neurological disorders. Previous studies have primarily been based on freshly harvested grafts, permitting only limited control over cells prior to transplantation. Here, we demonstrate the ability of in vitro expanded hematopoietic stem and progenitor cells (cHSPCs) to engraft in the myeloid niche of the brain, and effectively replace endogenous microglia both in vivo and in vitro. This experiment compares the transcriptional profile of cHSPCs, cultured endogenous microglia, and cHSPCs-derived myeloid cells (HDMCs).
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Project description:The replacement of microglia with myeloid cells derived from transplanted bone marrow represents a promising cell therapeutic concept for different neurological disorders. Previous studies have primarily been based on freshly harvested grafts, permitting only limited control over cells prior to transplantation. Here we demonstrate the ability of in vitro expanded hematopoietic stem and progenitor cells (cHSPCs) to engraft in the myeloid niche of the brain, and effectively replace endogenous microglia both in vivo and in vitro. Utilizing genetic editing of cHSPCs, we identify elongator acetyltransferase complex subunit 1 (Elp1; also known as Ikbkap; encoding for the protein IKAP) as an essential gene for the generation of cHSPC-derived myeloid cells (HDMCs). In accordance with its role as a subunit of the Elongator complex, loss of Elp1 in early-stage HDMCs led to upregulation of a gene module associated with the unfolded protein response.
2026-07-18 | PXD049985 | Pride
Project description:The replacement of microglia with myeloid cells derived from transplanted bone marrow represents a promising cell therapeutic concept for different neurological disorders. Previous studies have primarily been based on freshly harvested grafts, permitting only limited control over cells prior to transplantation. Here we demonstrate the ability of in vitro expanded hematopoietic stem and progenitor cells (cHSPCs) to engraft in the myeloid niche of the brain, and effectively replace endogenous microglia both in vivo and in vitro. Utilizing genetic editing of cHSPCs, we identify elongator acetyltransferase complex subunit 1 (Elp1; also known as Ikbkap; encoding for the protein IKAP) as an essential gene for the generation of cHSPC-derived myeloid cells (HDMCs). In accordance with its role as a subunit of the Elongator complex, loss of Elp1 in early-stage HDMCs led to upregulation of a gene module associated with the unfolded protein response.
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Project description:Murine WBP1L-deficient (Wbp1l-/-) hematopoietic stem and progenitor cells engraft significantly better than wild-type (WT) cells in competitive transplantation assays. To analyze the mechanism, Wbp1l-/- or WT bone marrow cells (both Ly5.2+Ly5.1-) were each mixed 1:1 with WT competitor cells (Ly5.2+Ly5.1+) and the mixture was transplanted into the lethally irradiated recipient mice. 22 weeks after the transplantation the donor Ly5.2+Ly5.1- LSK cells (Wbp1l-/- or WT) were purified from the bone marrow of recipient mice, RNA was extracted and subjected to RNA sequencing.
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Project description:<p>We are studying the natural history, pathogenesis and treatment of patients with WHIM syndrome, an immunodeficiency disorder characterized by warts, hypogammaglobulinemia, recurrent infections and neutropenia usually due to autosomal dominant gain-of-function mutations in chemokine receptor <i>CXCR4</i>. We have identified a patient born with WHIM syndrome and the WHIM mutation <i>CXCR4<sup>R334X</sup></i> who has been disease-free for 20 years and who lacks <i>CXCR4<sup>R334X</sup></i> in myeloid cells, the cells that drive disease manifestations. She is a genetic and hematopoietic mosaic, since she still has the mutation in lymphoid cells and non-hematopoietic cells. Cytogenetics and microarray analysis revealed that the mechanism of loss of the mutation was deletion of the mutant allele from one copy of chromosome 2. Whole genome sequencing of patient neutrophil and skin fibroblast genomic DNA revealed that the mechanism of deletion was chromothripsis, a process of chromosome shattering resulting in deletions and rearrangements of the non-deleted chromosomal segments. In the patient, this process evidently occurred in a single hematopoietic stem cell (HSC), resulting in deletion of the disease allele <i>CXCR4<sup>R334X</sup></i> and one copy of 163 other genes on chromosome 2. This HSC evidently acquired a growth advantage and repopulated the HSC population and the myeloid lineage. Consistent with this, studies using gene targeted mice in competitive bone marrow transplantation experiments revealed that selective <i>Cxcr4</i> haploinsufficiency (inactivation of one copy of <i>Cxcr4</i> and not of any other genes) was sufficient to confer a strong engraftment advantage over bone marrow cells from wild type mice as well as bone marrow cells from a mouse model of WHIM syndrome. These results suggest that <i>CXCR4</i> knockdown may be a useful strategy to enhance bone marrow engraftment in the absence of toxic bone marrow conditioning regimens.</p>
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Project description:Hematopoietic stem/progenitor cells (HSPCs) have been successfully used in treating malignancies but with limited cell sources. Whether circulating HSPCs (cHSPCs) in nonmobilized peripheral blood (PB) with engraftment capability could be expanded remains elusive. Here, we developed a polypeptide three-dimensional culture system (3DCS) to expand cHSPCs in nonmobilized PB. We demonstrated that cHSPCs exhibited self-renewal and multilineage differentiation potential by in vitro and in vivo assays including serial transplantation assays. Moreover, we found that 3DCS-derived cHSPCs increased by ~10-fold in vitro and by more than 300-fold in vivo. Bulk RNA-Seq and high-throughput qRT-PCR revealed that cHSPCs showed expression patterns that were similar to those of bone marrow-derived CD34+ HSPCs. Single-cell RNA-Seq elucidated that the 3DCS produced a milieu of immunosuppression that included heterogenous HSPCs and Treg cells. Cytokine arrays illustrated that that 3DCS secreted cytokines, including TNF-α essential for HSPC survival. In conclusion, 3DCS facilitates the expansion of cHSPCs with repopulating capabilities, providing cells for personalized precision medicine.
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Project description:After irradiation and bone-marrow transplantation, most of microglia and boarder-associated macrophages in the central nervous system is replaced by engranft cells. Taking advantages of Ms4a3-Cre: R26-TdTomato: Cx3cr1-gfp mice, we discriminated cells from monocyte precursors and hematopoietic stem cells with colors at 32 weeks following irradiation and bone-marrow transplantation. We sorted HSC-derived, monocyte-derived, and endogenouse microglia and leptomeningeal macrophages, and analyzed gene expression level between different cell populations using a bulk RNAseq method.
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Project description:Current therapies for metastatic colorectal cancer only prolong life for approximately 2 years. A more innovative therapy that prolongs life significantly or even cures is needed. Bone marrow transplantation is a curative therapy for patients with leukemias and lymphomas. Tumor eradication in the case of transplantation of the patient’s own marrow (autologous transplantation) is based on the intensive chemotherapy and/or radiotherapy used for conditioning. Tumor eradication in the case of transplantation using the marrow of a normal donor is based on both tumor reduction from conditioning and the immune elimination of tumor cells by T cells in the donor transplant that recognize the foreign tissue antigens expressed by the tumor cells and kill these cells. The use of bone marrow transplantation to treat tumors other than leukemia and lymphoma has been limited, and studies of transplantation of the patient’s own marrow for the treatment of advanced /metastatic breast cancer have not conclusively shown benefit beyond conventional therapy.
Recently, the Strober lab developed a preclinical model that effectively treated colon cancer in mice by combining immunotherapy and autologous bone marrow transplantation in order to markedly augment the anti-tumor potency of immunotherapy. They used the CT26 colon cancer as the therapeutic target either as a single subcutaneous tumor nodule, as a disseminated tumor in the lungs and peritoneum, or as a metastatic tumor in the liver depending on the route of administration of the tumor cells in BALB/c mice. Mice were vaccinated mice with established primary tumors or disseminated/ metastatic disease with irradiated tumor cells mixed with the adjuvant CpG, and found that vaccination alone had no effect on tumor growth. Similarly radiation conditioning of tumor bearing hosts followed by transplantation of bone marrow and spleen cells or purified T cells and hematopoietic stem cells from unvaccinated donors of the same strain had no effect. In contrast, radiation conditioning of mice followed by transplantation of hematopoietic and immune cells from donors of the same strain vaccinated with tumor cells and CpG cured almost all subcutaneous primary as well as disseminated and metastatic tumors in the hosts. A similar result was obtained after autologous transplantation of hematopoietic and immune cells from tumor bearing mice that had been vaccinated after tumor establishment. Investigation of tumor infiltrating cells showed that the injected donor T cells do not accumulate in the tumors unless the host has been irradiated before injection.
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