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Premature senescence impairs hematopoietic stem cell function during sickle cell disease in mice and humans (Mouse Bulk RNA-Seq)

ABSTRACT: Curative therapies using autologous genetically modified hematopoietic stem and progenitor cells (HSPCs) are now FDA-approved for sickle cell disease (SCD). However, there are concerns that the pathophysiology of SCD may degrade the quality of HSPCs required for these cellular therapies. We interrogated the phenotype and function of HSPCs in mice and individuals with SCD. We observed elevated cycling, DNA damage, reactive oxygen species, and hallmarks of senescence in bone marrow HSPCs from SCD mice, which correlated with a loss of long-term repopulating HSPCs. Bone marrow HSPCs from individuals with SCD also display hallmarks of senescence and diminished function. Transcriptomic profiling of mouse and human HSPCs revealed reduced expression of genes regulating cell cycle, DNA replication, and DNA repair, consistent with senescence. Treatment of SCD mice with the senolytic, ABT-263 (Navitoclax), increased HSPC frequency, restored HSPC transplantation activity, and decreased numbers of HSPCs with DNA damage. Thus, we demonstrate that stress-associated loss of function in the bone marrow of mice and individuals with SCD is reversible with senolytic therapy. Our work suggests a strategy for improving the function and fidelity of HSPCs collected for autologous gene therapy, which could further improve the efficacy and safety of these curative therapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE277683 | GEO | 2026/07/22

REPOSITORIES: GEO

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Project description:The occurrence of clonal perturbations and leukemia in patients transplanted with retrovirally-transduced autologous hematopoietic stem and progenitor cells (HSPCs) has stimulated extensive investigation, demonstrating that proviral insertions perturb adjacent proto-oncogene expression. Although enhancer-deleted lentiviruses are less likely to result in insertional oncogenesis, there is evidence that they may perturb transcript splicing, and one patient with a benign clonal expansion of lentivirally-transduced HPSC has been reported. The rhesus macaque model provides an opportunity for informative long-term analysis to ask whether transduction impacts on long-term HSPC properties. We utilized two techniques to examine whether lentivirally-transduced HSPCs from eight rhesus macaques transplanted 1-13.5 years previously are perturbed at a population level, comparing telomere length as a measure of replicative history and gene expression profile of vector positive versus vector negative cells. There were no differences in telomere lengths between sorted GFP+ and GFP- blood cells, suggesting that lentiviral transduction did not globally disrupt replicative patterns. Bone marrow GFP+ and GFP- CD34+ cells showed no differences in gene expression using unsupervised and principal component analysis. These studies did not uncover any global long-term perturbation of proliferation, differentiation, or other important functional parameters of transduced HSPCs in the rhesus macaque model. CD34+ hematopoietic stem and progenitor cells were purified from bone marrow aspirates obtained from 4 rhesus macaques 3-9 years following transplantation with lentivirally-transduced autologous hematopoietic stem and progenitor cells. All lentiviral vectors contained the GFP marker gene. The CD34+ cells from each animal were sorted via flow cytometry into GFP+ and GFP- fractions, and RNA from these cells was used for Affymetrix gene expression analysis as detailed below. There were two samples, GFP+ and GFP-, from each of 4 animals.

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Premature senescence impairs hematopoietic stem cell function during sickle cell disease in mice and humans (Mouse Bulk RNA-Seq)

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