Asymmetrically Segregated Mitochondria Provide Cellular Memory of Hematopoietic Stem Cell Replicative History and Drive HSC Attrition

Hinge, Ashwini; He, Jingyi; Bartram, James; Javier, Jose; Xu, Juying; Fjellman, Ellen; Sesaki, Hiromi; Li, Tingyu; Yu, Jinming; Wunderlich, Mark; Mulloy, James C.; Kofron, Matthew; Salomonis, Nathan; Grimes, H. Leighton; Filippi, Marie Dominique

doi:10.1016/j.stem.2020.01.016

Cited by 131 publications

(126 citation statements)

References 45 publications

(65 reference statements)

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“…In addition to the translational mechanisms presented here, it has been proposed that mechanical force-mediated Ca 2+ signals in response to cell shrinkage induced by hyperosmotic stress can be a potential mechanism for mitochondria fragmentation in osmoadaptation (Kim et al, 2015). The high percentage of mitochondria fragmentation in APR, which was paralleled by a dramatic decrease in the mitochondrial membrane potential and translational pausing of nuclear-encoded mitochondria mRNAs, may be similar to the recently reported requirements of mitochondria fission and low metabolic activity as a mechanism to preserve cellular integrity and self-renewal of hematopoietic stem cells (Hinge et al, 2020;Liang et al, 2020).…”

Section: Discussionsupporting

confidence: 76%

Adaptive translational pausing is a hallmark of the cellular response to severe environmental stress

Jobava¹,

Mao

Guan³

et al. 2020

Preprint

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SummaryMammalian cells have to adapt to environmental challenges that range from mild to severe stress. While the cellular response to mild stress has been widely studied, how cells respond to severe stress remains unclear. We show here that under severe stress conditions, cells induce a transient hibernation-like mechanism that anticipates recovery. We demonstrate that this Adaptive Pausing Response (APR) is a coordinated cellular response that limits ATP supply and consumption though mitochondrial fragmentation and widespread pausing of mRNA translation. This pausing is accomplished by ribosome stalling at translation initiation codons, which keeps mRNAs poised to resume translation upon recovery from severe stress. We further show that recovery from severe stress involves adaptive ISR (Integrated Stress Response) signaling that in turn permits cell cycle progression, resumption of growth, and reversal of mitochondria fragmentation. Our findings indicate that cells can respond to severe stress through the APR, a mechanism that preserves vital elements of cellular function under harsh environmental conditions.

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Section: Discussionsupporting

confidence: 76%

Adaptive translational pausing is a hallmark of the cellular response to severe environmental stress

Jobava¹,

Mao

Guan³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…For example, the quality of mitochondria in HSCs is regulated by fission/fusion and mitophagy-mediated mitochondrial quality control systems which segregate and remove the damaged mitochondria using lysosomal degradation [ 57 , 140 , 141 ]. However, if the damaged mitochondria cannot be fully removed, then HSCs will distribute the damaged mitochondria to one of the mitotic daughters in order to assure that the healthy mitochondria present in the other daughter cell will preserve the number and function of HSCs [ 98 , 101 , 102 ]. In addition, the signaling pathways which mediate nuclear-mitochondrial communication, including NAD + -Sirt1-HIF-1α, Sirt7-NRF1 and Foxo/Sirt3-antioxidants (such as SOD2), also play critical roles in maintaining the low metabolic and inactive states of mitochondria by regulating redox reactions and the mitochondrial unfolding protein response (UPR) [ 124 , 126 , 129 – 131 , 142 , 143 ].…”

Section: Cell-intrinsic Mechanism Of Hsc Agingmentioning

confidence: 99%

Molecular and cellular mechanisms of aging in hematopoietic stem cells and their niches

et al. 2020

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Aging drives the genetic and epigenetic changes that result in a decline in hematopoietic stem cell (HSC) functioning. Such changes lead to aging-related hematopoietic/immune impairments and hematopoietic disorders. Understanding how such changes are initiated and how they progress will help in the development of medications that could improve the quality life for the elderly and to treat and possibly prevent aging-related hematopoietic diseases. Here, we review the most recent advances in research into HSC aging and discuss the role of HSC-intrinsic events, as well as those that relate to the aging bone marrow niche microenvironment in the overall processes of HSC aging. In addition, we discuss the potential mechanisms by which HSC aging is regulated.

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“…Many infections also cause stem and progenitor proliferation and loss of HSC (24)(25)(26). When HSC proliferate, they lose stem cell potential and can quickly become exhausted (38,39). Infection-induced HSPC mobilization might also be used to replenish empty niches in distal bones thus maintaining the normal HSC pool (40).…”

Section: Functional Consequences Of Infection In the Bone Marrowmentioning

confidence: 99%

The Role of the Bone Marrow Microenvironment in the Response to Infection

2020

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Hematopoiesis in the bone marrow (BM) is the primary source of immune cells. Hematopoiesis is regulated by a diverse cellular microenvironment that supports stepwise differentiation of multipotent stem cells and progenitors into mature blood cells. Blood cell production is not static and the bone marrow has evolved to sense and respond to infection by rapidly generating immune cells that are quickly released into the circulation to replenish those that are consumed in the periphery. Unfortunately, infection also has deleterious effects injuring hematopoietic stem cells (HSC), inefficient hematopoiesis, and remodeling and destruction of the microenvironment. Despite its central role in immunity, the role of the microenvironment in the response to infection has not been systematically investigated. Here we summarize the key experimental evidence demonstrating a critical role of the bone marrow microenvironment in orchestrating the bone marrow response to infection and discuss areas of future research.

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Asymmetrically Segregated Mitochondria Provide Cellular Memory of Hematopoietic Stem Cell Replicative History and Drive HSC Attrition

Cited by 131 publications

References 45 publications

Adaptive translational pausing is a hallmark of the cellular response to severe environmental stress

Adaptive translational pausing is a hallmark of the cellular response to severe environmental stress

Molecular and cellular mechanisms of aging in hematopoietic stem cells and their niches

The Role of the Bone Marrow Microenvironment in the Response to Infection

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