Single cell transcriptome profiling of Reticular Dysgenesis patient bone marrow
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE179346 | GEO | 2021/07/06
REPOSITORIES: GEO
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Project description:Reticular Dysgenesis (RD) is a rare but devastating form of severe combined immunodeficiency, characterized by a maturation arrest of the myeloid and lymphoid lineages paired with sensorineural hearing loss. RD is caused by biallelic loss-of-function mutations in the mitochondrial enzyme adenylate kinase 2 (AK2). To study the effect of AK2 depletion on HSPC differentiation, we developed a biallelic AK2 CRISPR knock-out model using human HSPCs. AK2 depleted HSPCs display severe proliferation and myeloid differentiation defects, recapitulating RD patient phenotype.
2021-07-06 | GSE179320 | GEO
Project description:Reticular dysgenesis (RD) is a human Severe Combined Immunodeficiency mainly characterized by a profound neutropenia and lymphopenia. This pathology is due to mutations in the adenylate kinase 2 (AK2) gene, resulting in the loss of AK2 protein expression. AK2 is a mitochondrial protein, which regulates the homeostasis of cellular adenine nucleotides by converting ADP into ATP and AMP. Using a RNA interference strategy, we dissected the role of AK2 during the commitment of hematopoietic progenitors towards the lymphoid or myeloid lineage. Our results demonstrated that AK2 knock-down progenitors have reduced proliferative and survival capacity and differentiation toward the lymphoid or granulocytic lineage is abrogated. In this report, we also highlighted that AK2 signaling pathway is essential to control energy production and to maintain the integrity of all mitochondrial functions. This steady state may be disturbed in RD patients leading to a blockade of the differentiation process.
2015-06-21 | E-MTAB-2680 | biostudies-arrayexpress
Project description:Recent studies have linked bioenergetic regulation to cellular differentiation. However, the contribution of metabolic communication among subcellular components to the fate of progenitor cells remains unclear. Adenylate kinase 2 (AK2) is an adenylate phosphotransferase localized in the mitochondrial intermembrane space. Although AK2 mutations in human can cause a severe combined immunodeficiency with neutropenia, named reticular dysgenesis (RD), underlying mechanisms have not yet been elucidated. To address these questions, we established induced pluripotent stem cells (iPSCs) from two RD patients. Metabolic flux analysis revealed that AK2 mediates the distribution of glycolytic metabolites into the tricarbon acid cycle in mitochondria. Hematopoietic differentiation from RD-iPSCs was profoundly impaired. Intriguingly, RD-iPSC-derived hematopoietic progenitors exhibited an immature mitochondrial morphology, discordant ATP distribution among the mitochondria and nucleus, and alteration of global transcriptional profiles. These results highlight the importance of stage-specific intracellular energy communication for controlling the fate of multipotential progenitors.
2018-09-03 | GSE76761 | GEO
Project description:Single cell transcriptome profiling of Reticular Dysgenesis patient bone marrow
| PRJNA743317 | ENA
Project description:Adenylate kinase 2 (AK2) is a wide-spread and highly conserved protein kinase whose main function is to catalyze the exchange of nucleotide phosphate groups. In this study, we showed that AK2 regulated tumor cell metastasis in lung adenocarcinoma. Positive expression of AK2 is related to lung adenocarcinoma progression and poor survival of patients. Knockdown or knockout of AK2 inhibited, while overexpression of AK2 promoted, human lung adenocarcinoma cell migration and invasion ability. Differential proteomics results showed that AK2 might be closely related to epithelial-mesenchymal transition (EMT). Further research indicated that AK2 regulated EMT occurrence through the Smad-dependent classical signaling pathways as measured by western blot and qPCR assays. Additionally, in vivo experiments showed that AK2-knockout in human lung tumor cells reduced their EMT-like features and formed fewer metastatic nodules both in liver and in lung tissues. In conclusion, we uncover a cancer metastasis-promoting role for AK2 and provide a rationale for targeting AK2 as a potential therapeutic approach for lung cancer.
2021-09-18 | PXD028247 | Pride
Project description:The adenosine analogue remdesivir has emerged as a front-line antiviral treatment for SARS-CoV-2, with preliminary evidence that it reduces the duration and severity of illness. As clinical trials are ongoing, the full side effect profile of remdesivir is not yet known. Prior clinical studies have identified adverse events, and remdesivir has been shown to inhibit mitochondrial RNA polymerase in biochemical experiments, yet little is known about the specific genetic pathways involved in cellular remdesivir metabolism and cytotoxicity. Through genome-wide CRISPR/Cas9 screening (data not provided here) and RNA sequencing, we identify specific genes and pathways implicated in remdesivir metabolism. We show that remdesivir treatment leads to a global repression of mitochondrial respiratory activity. Further, we show that loss of the mitochondrial nucleoside transporter SLC29A3 or the mitochondrial adenylate kinase AK2 provide 10-72-fold mitigation of remdesivir toxicity while conserving its antiviral potency. This work provides candidate gene targets to reduce remdesivir toxicity and provides a proof-of-principle for the use of CRISPR/Cas9 screening to elucidate mechanisms of drug cytotoxicity.
2020-09-08 | GSE154936 | GEO
Project description:homozygosity mapping in a family with ovarian failure Two affected and four unafected siblings from consanguineous family were studied to identify shared regions of homozygosity in affected females with gonadal dysgenesis
2014-10-16 | E-GEOD-62347 | biostudies-arrayexpress
Project description:Efficient germinal center formation requires the coordinated movement of B cells between distinct regions of the B cell follicle where their fate and function is governed by the integration of cues from their interacting partners. While CXCL13 is known to be important for B cell chemoattraction and follicle formation, the molecular identity of B cell-interacting reticular cells remains ill-defined. Moreover, how CXCL13-expressing, B-cell interacting reticular cells are reprogramed to cater to the developing germinal center remains unclear. Here we use the Cxcl13-Cre/TdTomato mouse model to genetically target and decipher the cellular composition of lymph node CXCL13-expressing reticular cells under steady-state and inflammatory conditions. Moreover, we examine the consequence of cell-specific, genetic perturbation of CXCL12 on the molecular identity of the reticular cell network. Transcriptomic analyses revealed that B cell follicle reticular cell subset specification is predetermined in the steady-state, although additional transcriptional changes accompany germinal center formation. Although genetic perturbation of CXCL12 alters GC topology, the molecular identity of the underlying reticular cells remains largely unperturbed.
2020-05-12 | E-MTAB-8445 | biostudies-arrayexpress
Project description:We report the transcriptome of subsets of mouse splenic mesenchymal reticular cells and lymph node reticular cells obtained from healthy Ccl19-cre x R26R-EYFP mice on a C57BL/6 background. We also examine splenic reticular cells from these mice infected with lymphocytic choriomeningitis virus (LCMV) strain Armstrong (acute infection) or strain Clone 13 (chronic infection). Subsets of CD45- CD31- Ter119- reticular cells were analyzed including PDPN+ T zone reticular cells (TRC) and MAdCAM-1+ marginal reticular cells (MRC) from spleen and lymph nodes. Additionally from the spleen we analyzed PDPN+ CD140a- cells, PDPN+ EYFP- cells, and EYFP+ red pulp reticular cells (RPRC) in healthy mice. We analyzed TRC, MRC, PDPN+ EYFP- cells, and EYFP+ RPRC from mice infected with LCMV Armstrong or LCMV Clone-13 on day 8 or on day 30 after infection. Our study represents the first detailed analysis of splenic reticular cell transcriptomes in healthy and LCMV-infected mice, with biologic replicates, generated by RNA-sequencing. We find substantial differential gene expression across subsets of splenic and lymph node reticular cells. We reveal significant changes in gene expression induced after virus infection that differ markedly with disease.
2022-01-09 | GSE171124 | GEO
Project description:Reticular dysgenesis (RD) is a rare congenital disorder defined clinically by the combination of severe combined immunodeficiency (SCID), agranulocytosis, and sensorineural deafness. Mutations in the gene encoding adenylate kinase 2 were identified to cause the disorder. Hematopoietic stem cell transplantation (HSCT) is the only option to cure this otherwise fatal disease. Retrospective data on clinical presentation, genetics, and outcome of HSCT were collected from centers in Europe, Asia, and North America for a total of 32 patients born between 1982 and 2011. Age at presentation was <4 weeks in 30 of 32 patients (94%). Grafts originated from mismatched family donors in 17 patients (55%), from matched family donors in 6 patients (19%), and from unrelated marrow or umbilical cord blood donors in 8 patients (26%). Thirteen patients received secondary or tertiary transplants. After transplantation, 21 of 31 patients were reported alive at a mean follow-up of 7.9 years (range: 0.6-23.6 years). All patients who died beyond 6 months after HSCT had persistent or recurrent agranulocytosis due to failure of donor myeloid engraftment. In the absence of conditioning, HSCT was ineffective to overcome agranulocytosis, and inclusion of myeloablative components in the conditioning regimens was required to achieve stable lymphomyeloid engraftment. In comparison with other SCID entities, considerable differences were noted regarding age at presentation, onset, and type of infectious complications, as well as the requirement of conditioning prior to HSCT. Although long-term survival is possible in the presence of mixed chimerism, high-level donor myeloid engraftment should be targeted to avoid posttransplant neutropenia.
| S-EPMC5445572 | biostudies-literature