RESUMO
During X chromosome inactivation (XCI), the inactive X chromosome (Xi) is recruited to the nuclear lamina at the nuclear periphery. Beside X chromosome reactivation resulting in a highly penetrant aging-like hematopoietic malignancy, little is known about XCI in aged hematopoietic stem cells (HSCs). Here, we demonstrate that LaminA/C defines a distinct repressive nuclear compartment for XCI in young HSCs, and its reduction in aged HSCs correlates with an impairment in the overall control of XCI. Integrated omics analyses reveal higher variation in gene expression, global hypomethylation, and significantly increased chromatin accessibility on the X chromosome (Chr X) in aged HSCs. In summary, our data support the role of LaminA/C in the establishment of a special repressive compartment for XCI in HSCs, which is impaired upon aging.
Assuntos
Senescência Celular/genética , Células-Tronco Hematopoéticas/metabolismo , Inativação do Cromossomo X/genética , Animais , Cromatina/metabolismo , Sequenciamento de Cromatina por Imunoprecipitação , Humanos , Lamina Tipo A/metabolismo , Camundongos Endogâmicos C57BL , Transposases/metabolismo , Cromossomo X/genéticaRESUMO
With ageing, intrinsic haematopoietic stem cell (HSC) activity decreases, resulting in impaired tissue homeostasis, reduced engraftment following transplantation and increased susceptibility to diseases. However, whether ageing also affects the HSC niche, and thereby impairs its capacity to support HSC function, is still widely debated. Here, by using in-vivo long-term label-retention assays we demonstrate that aged label-retaining HSCs, which are, in old mice, the most quiescent HSC subpopulation with the highest regenerative capacity and cellular polarity, reside predominantly in perisinusoidal niches. Furthermore, we demonstrate that sinusoidal niches are uniquely preserved in shape, morphology and number on ageing. Finally, we show that myeloablative chemotherapy can selectively disrupt aged sinusoidal niches in the long term, which is linked to the lack of recovery of endothelial Jag2 at sinusoids. Overall, our data characterize the functional alterations of the aged HSC niche and unveil that perisinusoidal niches are uniquely preserved and thereby protect HSCs from ageing.
Assuntos
Envelhecimento/genética , Capilares/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Homeostase/genética , Nicho de Células-Tronco/genética , Envelhecimento/metabolismo , Animais , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Capilares/citologia , Capilares/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Polaridade Celular/efeitos dos fármacos , Rastreamento de Células/métodos , Doxiciclina/farmacologia , Fluoruracila/farmacologia , Regulação da Expressão Gênica , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Histonas/genética , Histonas/metabolismo , Homeostase/efeitos dos fármacos , Proteína Jagged-2/genética , Proteína Jagged-2/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Agonistas Mieloablativos/farmacologia , Nicho de Células-Tronco/efeitos dos fármacosRESUMO
The spindle assembly checkpoint plays a pivotal role in preventing aneuploidy and transformation. Many studies demonstrate impairment of this checkpoint in cancer cells. While leukemia is frequently driven by transformed hematopoietic stem and progenitor cells (HSPCs), the biology of the spindle assembly checkpoint in such primary cells is not very well understood. Here, we reveal that the checkpoint is fully functional in murine progenitor cells and, to a lesser extent, in hematopoietic stem cells. We show that HSPCs arrest at prometaphase and induce p53-dependent apoptosis upon prolonged treatment with anti-mitotic drugs. Moreover, the checkpoint can be chemically and genetically abrogated, leading to premature exit from mitosis, subsequent enforced G1 arrest, and enhanced levels of chromosomal damage. We finally demonstrate that, upon checkpoint abrogation in HSPCs, hematopoiesis is impaired, manifested by loss of differentiation potential and engraftment ability, indicating a critical role of this checkpoint in HSPCs and hematopoiesis.
