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1.
Nature ; 543(7644): 205-210, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28241143

RESUMO

With age, haematopoietic stem cells lose their ability to regenerate the blood system, and promote disease development. Autophagy is associated with health and longevity, and is critical for protecting haematopoietic stem cells from metabolic stress. Here we show that loss of autophagy in haematopoietic stem cells causes accumulation of mitochondria and an activated metabolic state, which drives accelerated myeloid differentiation mainly through epigenetic deregulations, and impairs haematopoietic stem-cell self-renewal activity and regenerative potential. Strikingly, most haematopoietic stem cells in aged mice share these altered metabolic and functional features. However, approximately one-third of aged haematopoietic stem cells exhibit high autophagy levels and maintain a low metabolic state with robust long-term regeneration potential similar to healthy young haematopoietic stem cells. Our results demonstrate that autophagy actively suppresses haematopoietic stem-cell metabolism by clearing active, healthy mitochondria to maintain quiescence and stemness, and becomes increasingly necessary with age to preserve the regenerative capacity of old haematopoietic stem cells.


Assuntos
Autofagia , Autorrenovação Celular , Senescência Celular , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/fisiologia , Animais , Autofagia/genética , Autorrenovação Celular/genética , Senescência Celular/genética , Epigênese Genética , Feminino , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Masculino , Camundongos , Mitocôndrias/metabolismo , Células Mieloides/citologia , Células Mieloides/metabolismo
2.
bioRxiv ; 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39314376

RESUMO

Hematopoietic stem and progenitor cells (HSPC) are regulated by interactions with stromal cells in the bone marrow (BM) cavity, which can be segregated into two spatially defined central marrow (CM) and endosteal (Endo) compartments. However, the importance of this spatial compartmentalization for BM responses to inflammation and neoplasia remains largely unknown. Here, we extensively validate a combination of scRNA-seq profiling and matching flow cytometry isolation that reproducibly identifies 7 key CM and Endo populations across mouse strains and accurately surveys both niche locations. We demonstrate that different perturbations exert specific effects on different compartments, with type I interferon responses causing CM mesenchymal stromal cells to adopt an inflammatory phenotype associated with overproduction of chemokines modulating local monocyte dynamics in the surrounding microenvironment. Our results provide a comprehensive method for molecular and functional stromal characterization and highlight the importance of altered stomal cell activity in regulating hematopoietic responses to inflammatory challenges.

3.
Nat Cell Biol ; 25(1): 30-41, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36650381

RESUMO

Haematopoietic ageing is marked by a loss of regenerative capacity and skewed differentiation from haematopoietic stem cells (HSCs), leading to impaired blood production. Signals from the bone marrow niche tailor blood production, but the contribution of the old niche to haematopoietic ageing remains unclear. Here we characterize the inflammatory milieu that drives both niche and haematopoietic remodelling. We find decreased numbers and functionality of osteoprogenitors at the endosteum and expansion of central marrow LepR+ mesenchymal stromal cells associated with deterioration of the sinusoidal vasculature. Together, they create a degraded and inflamed old bone marrow niche. Niche inflammation in turn drives the chronic activation of emergency myelopoiesis pathways in old HSCs and multipotent progenitors, which promotes myeloid differentiation and hinders haematopoietic regeneration. Moreover, we show how production of interleukin-1ß (IL-1ß) by the damaged endosteum acts in trans to drive the proinflammatory nature of the central marrow, with damaging consequences for the old blood system. Notably, niche deterioration, HSC dysfunction and defective regeneration can all be ameliorated by blocking IL-1 signalling. Our results demonstrate that targeting IL-1 as a key mediator of niche inflammation is a tractable strategy to improve blood production during ageing.


Assuntos
Medula Óssea , Células-Tronco Hematopoéticas , Medula Óssea/metabolismo , Diferenciação Celular , Hematopoese , Células-Tronco Hematopoéticas/metabolismo , Nicho de Células-Tronco , Interleucina-1/metabolismo
4.
J Exp Med ; 218(7)2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34032859

RESUMO

While young blood can restore many aged tissues, its effects on the aged blood system itself and old hematopoietic stem cells (HSCs) have not been determined. Here, we used transplantation, parabiosis, plasma transfer, exercise, calorie restriction, and aging mutant mice to understand the effects of age-regulated systemic factors on HSCs and their bone marrow (BM) niche. We found that neither exposure to young blood, nor long-term residence in young niches after parabiont separation, nor direct heterochronic transplantation had any observable rejuvenating effects on old HSCs. Likewise, exercise and calorie restriction did not improve old HSC function, nor old BM niches. Conversely, young HSCs were not affected by systemic pro-aging conditions, and HSC function was not impacted by mutations influencing organismal aging in established long-lived or progeroid genetic models. Therefore, the blood system that carries factors with either rejuvenating or pro-aging properties for many other tissues is itself refractory to those factors.


Assuntos
Envelhecimento/fisiologia , Células-Tronco Hematopoéticas/citologia , Rejuvenescimento/fisiologia , Animais , Medula Óssea/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Mutação/genética
5.
Trends Mol Med ; 25(6): 494-515, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31109796

RESUMO

Aging leads to functional decline of the hematopoietic system, manifested by an increased incidence of hematological disease in the elderly. Deterioration of hematopoietic integrity with age originates in part from the degraded functionality of hematopoietic stem cells (HSCs). Here, we review recent findings identifying changes in metabolic programs and loss of epigenetic identity as major drivers of old HSC dysfunction and their role in promoting leukemia onset in the context of age-related clonal hematopoiesis (ARCH). We discuss how inflammatory and growth signals from the aged bone marrow (BM) microenvironment contribute to cell-intrinsic HSC aging phenotypes and favor leukemia development. Finally, we address how metabolic, epigenetic, and inflammatory pathways could be targeted to enhance old HSC fitness and prevent leukemic transformation.


Assuntos
Microambiente Celular , Senescência Celular , Células-Tronco Hematopoéticas/metabolismo , Animais , Biomarcadores , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Senescência Celular/genética , Desenho de Fármacos , Metabolismo Energético , Epigênese Genética , Regulação da Expressão Gênica , Hematopoese , Células-Tronco Hematopoéticas/citologia , Humanos , Leucemia/etiologia , Leucemia/metabolismo , Leucemia/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Transdução de Sinais , Microambiente Tumoral
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