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Y-H. Ho and S. Méndez-Ferrer et al.
shows higher affinity for noradrenaline over adrenaline, the opposite is true for β2-AR.117 Another possibility might be that BM concentrations of both neurotransmitters dif- fer in aging, leading to imbalanced stimulation of the two receptors. The observation that old HSC home in the BM away from endosteal regions suggests that HSC-driven niche remodeling mainly occurs in non-endosteal domains. For instance, skewed myelopoiesis leading to increased numbers of neutrophils and defective phagocy- tosis of marrow macrophages might modulate the microenvironment favoring myeloid bias during aging.81 Increased myeloid cells might provide an additional source of catecholamines in a feed-forward loop promot- ing megakaryocyte differentiation by activating β2-AR. We propose that accumulation of old HSC results in microenvironmental remodeling by reinforcing adrenergic activity, expansion of non-endosteal niches and enhanced myeloid/megakaryocyte differentiation. As a secondary outcome, alteration of megakaryocyte niches (increased megakaryocyte numbers, proplatelet formation and appo- sition to sinusoids) might release HSC from their state of quiescence, further promoting HSC proliferation with age.
Niche alterations might predispose to hematologic neoplasms
The risk of developing myeloid malignancies increases significantly in individuals harboring clonal hematopoiesis-related somatic mutations. In fact some of these mutations are oncogenic drivers of myeloid malig- nancies.118 However, the factors limiting clonal expansion or, instead, allowing the mutant clones to become domi- nant and, in some cases, cause disease, remain unclear. Interestingly, similar niche alterations are shared between aging and myeloid disorders associated with age, which is
an important selection pressure to expand aberrant HSC clones. For instance, a damaged neuro-MSC circuit pro- motes the development of a cytokine storm created by the mutant HSC, aggravating the progression of myeloprolif- erative neoplasms.75 In myelodysplastic syndromes, abnormal production of cytokines from the microenviron- ment, dysfunction of MSC and osteolineage cells, and vas- cular remodeling have been associated with disease initia- tion and progression.119,120 Targeting the abnormal microen- vironment could be a promising complementary thera- peutic approach to treat hematologic cancers in the future, especially when early diagnosis becomes available.
Conclusive remarks
Aging of the hematopoietic system might result from both HSC-intrinsic and microenvironmental alterations with changes in the location, function and regulation of HSC and their progeny. Future studies will determine the relative contribution of the aged microenviroment to altered hematopoiesis and increased incidence of age- related disorders originating in the BM.
Acknowledgments
Y-HH received fellowships from Alborada Scholarship (University of Cambridge), Trinity-Henry Barlow Scholarship (University of Cambridge) and R.O.C. Government Scholarship to Study Abroad (GSSA). This work was supported by core sup- port grants from the Wellcome Trust and the MRC to the Cambridge Stem Cell Institute, National Health Service Blood and Transplant (United Kingdom), European Union’s Horizon 2020 research (ERC-2014-CoG-64765) and a Programme Foundation Award from Cancer Research UK to SM-F The authors regret that some relevant literature could not be discussed because of space constrictions.
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