Endothelial mTOR maintains hematopoiesis during aging

Ramalingam, Pradeep; Poulos, Michael G.; Gutkin, Michael; Katsnelson, Lizabeth; Freire, Ana G.; Lazzari, Elisa; Butler, Jason M.

doi:10.1084/jem.20191212

Cited by 21 publications

(13 citation statements)

References 73 publications

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“…BM ECs, expressing high level of Tlr4 and myeloid primary response gene 88 (Myd88), are the primary source of granulocyte colony-stimulating factor (G-CSF), the key granulopoietic cytokine, after LPS challenge or Escherichia coli infection. Therefore, ECs are essential cells for emergency granulopoiesis under systemic bacterial infection [98]. Consistent with this, young HSPCs cocultured on aged ECs acquired a myeloid bias with a decrease in B and T cell frequencies, and an in vivo infusion of aged endothelium into young recipients impaired HSC self-renewal and induced myeloid bias [65].…”

Section: Aged Bm Niche Is Inflamedsupporting

confidence: 53%

Inflammation and Aging of Hematopoietic Stem Cells in Their Niche

Yang

Haan

2021

Cells

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Hematopoietic stem cells (HSCs) sustain the lifelong production of all blood cell lineages. The functioning of aged HSCs is impaired, including a declined repopulation capacity and myeloid and platelet-restricted differentiation. Both cell-intrinsic and microenvironmental extrinsic factors contribute to HSC aging. Recent studies highlight the emerging role of inflammation in contributing to HSC aging. In this review, we summarize the recent finding of age-associated changes of HSCs and the bone marrow niche in which they lodge, and discuss how inflammation may drive HSC aging.

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Section: Aged Bm Niche Is Inflamedsupporting

confidence: 53%

Inflammation and Aging of Hematopoietic Stem Cells in Their Niche

Yang

Haan

2021

Cells

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“…Interestingly, specific HSC-supporting signalings are lost at the arteries. In particular, Jag2 expression is lost at arterial ECs (aECs) ( 40 ) and mTOR is downregulated ( 77 ). The sinusoidal niche preserves its structure and functionality, and sinusoidal ECs (sECs) maintain the signaling involved in the support of HSC functions.…”

Section: Aging Of the Bm Niche: Phenotypic And Functional Remodelingmentioning

confidence: 99%

“…Upon aging, ECs downregulate mTOR signaling, which induces a reduction in their support to hematopoiesis. Specific deletion of mTOR in ECs (mTOR (ECKO) mice) leads to loss of α-tubulin polarity, accumulation of γH2AX foci, and change in the transcriptome of HSCs, and transplantation of young HSCs in mTOR (ECKO) mice is sufficient to induce an aged phenotype in stem cells ( 77 ).…”

Section: Aging Of the Bm Niche: Phenotypic And Functional Remodelingmentioning

confidence: 99%

“…In fact, young mice upon BMEC specific deletion of mTOR display a premature aging phenotype with increased frequency of HSCs and myeloid cells and reduced lymphoid cells. Moreover, the same mouse model allowed the analysis of the vasculature in BMEC mTOR KO animals and to point out that the observed premature aging phenotype in HSPC was due to changes in the instructive signals arising from the endothelial niche, excluding a possible role for vascular degeneration, as the vasculature of knockout mice did not manifest gross alterations ( 77 ).…”

Section: Tools To Investigate the Aging Bm Nichementioning

confidence: 99%

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Aging of the Hematopoietic Stem Cell Niche: New Tools to Answer an Old Question

2021

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The hematopoietic stem cell (HSC) niche is a specialized microenvironment, where a complex and dynamic network of interactions across multiple cell types regulates HSC function. During the last years, it became progressively clearer that changes in the HSC niche are responsible for specific alterations of HSC behavior. The aging of the bone marrow (BM) microenvironment has been shown to critically contribute to the decline in HSC function over time. Interestingly, while upon aging some niche structures within the BM are degenerated and negatively affect HSC functionality, other niche cells and specific signals are preserved and essential to retaining HSC function and regenerative capacity. These new findings on the role of the aging BM niche critically depend on the implementation of new technical tools, developed thanks to transdisciplinary approaches, which bring together different scientific fields. For example, the development of specific mouse models in addition to coculture systems, new 3D-imaging tools, ossicles, and ex-vivo BM mimicking systems is highlighting the importance of new technologies to unravel the complexity of the BM niche on aging. Of note, an exponential impact in the understanding of this biological system has been recently brought by single-cell sequencing techniques, spatial transcriptomics, and implementation of artificial intelligence and deep learning approaches to data analysis and integration. This review focuses on how the aging of the BM niche affects HSCs and on the new tools to investigate the specific alterations occurring in the BM upon aging. All these new advances in the understanding of the BM niche and its regulatory function on HSCs have the potential to lead to novel therapeutical approaches to preserve HSC function upon aging and disease.

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“…Though once again, recent work is highlighting the different roles that these nutrient sensing pathways play in varying cell populations within a system, and in the niches in which they reside. For example, genetic loss of mTOR activity in the bone marrow microenvironment that informs HSC development can lead to aging phenotypes of both hematopoietic stem cells and progenitors [ 97 ]. Autophagy has also been shown to play an important role in HSC homeostasis and recently was shown to be impaired with age, leading to accumulation of active mitochondria and more metabolically active HSCs [ 98 ••].…”

Section: Metabolic Regulation Of Adult Stem Cells In Aging and Dietar...mentioning

confidence: 99%

Metabolic Regulation of Stem Cells in Aging

et al. 2021

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Purpose of Review From invertebrates to vertebrates, the ability to sense nutrient availability is critical for survival. Complex organisms have evolved numerous signaling pathways to sense nutrients and dietary fluctuations, which influence many cellular processes. Although both overabundance and extreme depletion of nutrients can lead to deleterious effects, dietary restriction without malnutrition can increase lifespan and promote overall health in many model organisms. In this review, we focus on age-dependent changes in stem cell metabolism and dietary interventions used to modulate stem cell function in aging. Recent Findings Over the last half-century, seminal studies have illustrated that dietary restriction confers beneficial effects on longevity in many model organisms. Many researchers have now turned to dissecting the molecular mechanisms by which these diets affect aging at the cellular level. One subpopulation of cells of particular interest are adult stem cells, the most regenerative cells of the body. It is generally accepted that the regenerative capacity of stem cells declines with age, and while the metabolic requirements of each vary across tissues, the ability of dietary interventions to influence stem cell function is striking. Summary In this review, we will focus primarily on how metabolism plays a role in adult stem cell homeostasis with respect to aging, with particular emphasis on intestinal stem cells while also touching on hematopoietic, skeletal muscle, and neural stem cells. We will also discuss key metabolic signaling pathways influenced by both dietary restriction and the aging process, and will examine their role in improving tissue homeostasis and lifespan. Understanding the mechanisms behind the metabolic needs of stem cells will help bridge the divide between a basic science interpretation of stem cell function and a whole-organism view of nutrition, thereby providing insight into potential dietary or therapeutic interventions.

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Endothelial mTOR maintains hematopoiesis during aging

Cited by 21 publications

References 73 publications

Inflammation and Aging of Hematopoietic Stem Cells in Their Niche

Inflammation and Aging of Hematopoietic Stem Cells in Their Niche

Aging of the Hematopoietic Stem Cell Niche: New Tools to Answer an Old Question

Metabolic Regulation of Stem Cells in Aging

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