Reduced repression of cytokine signaling ameliorates age‐induced decline in hematopoietic stem cell function

Norddahl, Gudmundurv L; Gisler, Santiago; Sigvardsson, Mikael; Bryder, David

doi:10.1111/j.1474-9726.2012.00863.x

Cited by 12 publications

(11 citation statements)

References 17 publications

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“…For example, enhanced cytokine signaling can counteract age-related HSC functional decline in the setting of loss of lymphocyte-specific adapter protein (LNK) deficiency in stem cells [53 ▪ ], whereas in the absence of the GAP junction formed by Connexin 43, HSCs are defective in unloading their reactive oxygen species onto niche cells and maintaining proper homeostasis under stress [54]. It is an intriguing possibility that niche factors might influence aging and clonality of HSCs and aging-associated progression of leukemia [54,55 ▪ ].…”

Section: Aging Of Hematopoietic Stem Cellsmentioning

confidence: 99%

Cdc42 and aging of hematopoietic stem cells

Geiger

Zheng

2013

Current Opinion in Hematology

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Purpose of review Hematopoietic stem cells (HSCs) continuously provide mature blood cells during the lifespan of a mammal. The functional decline in hematopoiesis in the elderly, which involves a progressive reduction in the immune response and an increased incidence of myeloid malignancy, is partly linked to HSC aging. Molecular mechanisms of HSC aging remain unclear, hindering rational approaches to slow or reverse the decline of HSC function with age. Identifying conditions under which aged HSCs become equivalent to young stem cells might result in treatments for age-associated imbalances in lymphopoiesis and myelopoiesis and in blood regeneration. Recent findings Aging of HSCs has been for a long time thought to be an irreversible process imprinted in stem cells due to the intrinsic nature of HSC aging. Mouse model studies have found that aging is associated with elevated activity of the Rho GTPase Cdc42 in HSCs that is causative for loss of polarity, altered epigenetic modifications and functional deficits of aged HSCs. The work suggests that inhibition of Cdc42 activity in aged HSCs may reverse a number of phenotypes associated with HSC aging. Summary Maintaining the regenerative capacity of organs or organ systems may be a useful way to ensure healthy aging. A defined set of features phenotypically separate young from aged HSCs. Aging of HSCs has been thought to be irreversible. Recent findings support the hypothesis that functional decline of aged HSCs may be reversible by pharmacological intervention of age altered signaling pathways and epigenetic modifications.

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Section: Aging Of Hematopoietic Stem Cellsmentioning

confidence: 99%

Cdc42 and aging of hematopoietic stem cells

Geiger

Zheng

2013

Current Opinion in Hematology

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“…[14][15][16] Affymetrix gene expression analysis RNA was extracted from 10 000 sorted HSCs (Lin -Sca1 1 c-Kit…”

Section: Telomere Length Measurementmentioning

confidence: 99%

An epigenetic component of hematopoietic stem cell aging amenable to reprogramming into a young state

Wahlestedt¹,

Norddahl²,

Sten³

et al. 2013

Blood

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103

106

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Key Points• Hematopoietic stem cell aging associates with stable transcriptional alterations.• Somatic cell reprogramming reverses functional defects associated with hematopoietic aging.Aging of hematopoietic stem cells (HSCs) leads to several functional changes, including alterations affecting self-renewal and differentiation. Although it is well established that many of the age-induced changes are intrinsic to HSCs, less is known regarding the stability of this state. Here, we entertained the hypothesis that HSC aging is driven by the acquisition of permanent genetic mutations. To examine this issue at a functional level in vivo, we applied induced pluripotent stem (iPS) cell reprogramming of aged hematopoietic progenitors and allowed the resulting aged-derived iPS cells to reform hematopoiesis via blastocyst complementation. Next, we functionally characterized iPS-derived HSCs in primary chimeras and after the transplantation of re-differentiated HSCs into new hosts, the gold standard to assess HSC function. Our data demonstrate remarkably similar functional properties of iPS-derived and endogenous blastocyst-derived HSCs, despite the extensive chronological and proliferative age of the former. Our results, therefore, favor a model in which an underlying, but reversible, epigenetic component is a hallmark of HSC aging. (Blood. 2013;121(21):4257-4264)

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“…Perhaps supporting this interpretation, the demonstration of increased levels of the inflammatory cytokine Rantes in the aging BM microenvironment was suggested to contribute to the age‐associated myeloid skewing [92]. In addition, we and others have found that the lack of the adaptor protein Lnk, which functions to dampen extrinsic cytokine signals, abrogates the phenotypes associated with HSC aging [93, 94]. Young as well as aged Lnk −/− mice display an expanded HSC pool.…”

Section: Is the Hsc Aging State Reversible?mentioning

confidence: 76%

“…Young as well as aged Lnk −/− mice display an expanded HSC pool. However, aged Lnk −/− HSCs harbored superior reconstitution potential compared with aged WT HSCs, with maintenance of a robust lymphoid differentiation potential [93, 94]. Recently, prolonged fasting was suggested to dampen the consequence of age on HSC function through normalization of the clonal distribution of the aging HSC compartment, that is, by reducing the frequency of myeloid‐biased HSCs and increasing the frequency of lymphoid‐biased HSCs [95].…”

Section: Is the Hsc Aging State Reversible?mentioning

confidence: 99%

Concise Review: Hematopoietic Stem Cell Aging and the Prospects for Rejuvenation

Pronk

Bryder

2014

Stem Cells Translational Medicine

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Because of the continuous increases in lifetime expectancy, the incidence of age-related diseases will, unless counteracted, represent an increasing problem at both the individual and socioeconomic levels. Studies on the processes of blood cell formation have revealed several shortcomings as a consequence of chronological age. They include a reduced ability to mount adaptive immune responses and a blood cell composition skewed toward myeloid cells, with the latter coinciding with a dramatically increased incidence of myelogenous diseases, including cancer. Conversely, the dominant forms of acute leukemia affecting children associate with the lymphoid lineages. A growing body of evidence has suggested that aging of various organs and cellular systems, including the hematopoietic system, associates with a functional demise of tissue-resident stem cell populations. Mechanistically, DNA damage and/or altered transcriptional landscapes appear to be major drivers of the hematopoietic stem cell aging state, with recent data proposing that stem cell aging phenotypes are characterized by at least some degree of reversibility. These findings suggest the possibility of rejuvenating, or at least dampening, stem cell aging phenotypes in the elderly for therapeutic benefit. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:186-194

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Reduced repression of cytokine signaling ameliorates age‐induced decline in hematopoietic stem cell function

Cited by 12 publications

References 17 publications

Cdc42 and aging of hematopoietic stem cells

Cdc42 and aging of hematopoietic stem cells

An epigenetic component of hematopoietic stem cell aging amenable to reprogramming into a young state

Concise Review: Hematopoietic Stem Cell Aging and the Prospects for Rejuvenation

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