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E. Mejia-Ramirez and M.C. Florian et al.
located in the ER that splices Xbp1 mRNA to a form that activates UPRER.133 Prolonged fasting has a direct effect on the UPRER system that influences the self-renewal and dif- ferentiation potential of stem cells.134 However, the effects of fasting in HSC have so far only been investigated from a different perspective. Prolonged fasting in mice protects HSC and progenitors within the bone marrow after chemotoxicity and promotes balanced hematopoietic regeneration, also in the absence of chemotherapy treat- ment. The effect of prolonged fasting on HSC is mediated by the low levels of expression of IGF1 (insulin-like growth factor 1) and PKAα in starved mice.135
Signaling pathways influencing intrinsic hematopoietic stem cell aging
Hematopoietic stem cells are located in a very special microenvironment: the bone marrow niche. Communication between the HSC and niche cells is essen- tial for a correct functioning of the whole hematopoietic system.136 Hence, it is very important that the signaling pathways between HSC and the niche are functioning cor- rectly throughout the life-span of the organisms. Since we are dealing here with intrinsic alterations of HSC upon aging, we will focus on some examples of signaling factors and pathways within stem cells that are particularly com- pelling in the context of intrinsic aging.
Tgf-β related
Transcriptome data analysis showed reduced TGF-β
signaling upon aging in HSC.15,28 Sun et al. calculated that TGF-β-regulated genes were five times more likely to be down-regulated compared to all other genes affected by age.28 Among the TGF-β downstream genes down-regu- lated in the study, more than half (63%) are related to bio- logical functions that somehow sustain hematopoiesis.43,137 In agreement with these findings, scATACseq experiments comparing young and old HSC have shown that TGF-β signaling is specifically enriched in young HSC, meaning that they are in a more accessible chromatin context, and consequently, more likely to be expressed in young when compared to old cells.15 TGF1- β signaling is also modulated by the regulation of the sta- bility of its receptor upon aging. Tif1-γ (transcription intermediary factor 1γ) regulates TGF1-βR turn over via its ubiquitin ligase activity. Tif1-γ was reported to be down-regulated in aged HSC, while knock out of Tif1-γ promoted premature HSC aging. Consequently, the amount of TGF1-βR is higher in aged HSC, making the cells more sensitive to TGF1-β.45
Wnt related
Wnt signaling has been described to have an important role in aging in different stem cell systems such as muscle stem cells, adult neural stem cells or skin stem cells.138-140 In the case of muscle stem cells, with age, canonical Wnt signaling is activated, leading to impaired muscle regener- ation and augmented fibrosis.139 For adult neural stem cells, it has been shown that aging leads to the overex- pression of the Wnt antagonist Dickkopf-1 in order to reduce neurogenesis. When Dickkopf-1 is conditionally ablated, neurogenesis increases.138 Regarding skin stem cells, the Wnt antagonist Klotho protects against aging by blocking Wnt signaling.140 Wnt family members also have
a role in bone marrow function, since different members are expressed in hematopoietic cells and in non- hematopoietic stromal cells.141 It has been shown that Wnt signaling is involved in the maintenance of the bal- ance between quiescence and activation of HSC in the bone marrow.40,142 In murine HSC, it has been shown that there is an intrinsic increased expression of Wnt5a, shift- ing the signaling from canonical to non-canonical in aged HSC.44 The non-canonical Wnt pathway resulted in Cdc42 activation and induced aging-like phenotypes when Wnt5a was added to young LT-HSC, including apo- larity and loss of epigenetic asymmetry at division.15,44 In contrast, the haploinsufficiency of Wnt5 showed attenu- ation of aging phenotypes in old HSC Wnt5a+/- mice.44 However, Wnt signaling in aging also has an extrinsic role in the bone marrow since haploinsufficient Wnt5a+/- recipient mice regenerate dysfunctional HSC upon sec- ondary transplantation.143 This apparent incongruence suggests that Wnt5a might exert both an autocrine and a paracrine effect on HSC.
Notch related
It is known that Notch is important for the mainte- nance of murine muscle stem cells since loss of Notch sig- naling pathway causes impairment in regeneration of muscle.144 In fact, the loss of satellite cells that occurs in aged mdx mice, a murine model for the Duchenne- Muscular-Disthropy that involves the downregulation of the Notch signaling pathway, can be ameliorated when
145
Notch signaling pathway is restored. Recently, it was
also demonstrated in murine muscle stem cells that lig- ands of Notch activate p53 during normal regeneration, while this axis is impaired in aged mice leading to cell death due to mitotic catastrophe.146
There is also evidence of the implication of Notch2, and not Notch1 in the specific Ventricular-subVentricular Zone (V-SVZ) adult neural stem cells, where it represses cell cycle preserving quiescence.147
In the case of the hematopoietic system, there are con- flicting results from different studies making this a subject of intense debate (reviewed by Lampreia42 and Weber and Calvi148). On one hand, the function of Notch signaling in murine HSC has been reported several times as favoring HSC self-renewal and expansion by in vitro stimulation of the Notch pathway, such as the transduction of the active intracellular portion of Notch1 or its targets, Hes1149,150 and in vivo by the deletion of a E3 ubiquitin ligase that nega- tively regulates Notch receptor degradation.151 However, most studies based on in vivo loss-of-function models seem to argue against these results, since Notch signaling pathway is not essential for adult hematopoiesis in mice.152,153 Notch involvement in human HSC function is also controversial.42 On one side, inhibition of Notch by transducing human HSCs with dnMAML1 leads to block- age of maintenance/expansion and T-cell development in vitro, while in vivo engraftment seems not to be affected.154 However, by using γ-secretase inhibitor (DAPT) to inhibit Notch signaling, it has been shown that Notch pathway is important for the repopulation capacity of human HSC.155
NF-kΒ related
Constitutive NF-kB activation has been involved in
aging in several murine tissues, including bone marrow,156 and in age-related myeloid malignancies like AML
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haematologica | 2020; 105(1)