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Title: Neuronal regulation of haematopoietic stem cell ageing and age-related blood disorders through the microenvironment
Author: Ho, Ya-Hsuan
ISNI:       0000 0004 8507 8113
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2020
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Haematopoietic stem cells (HSCs) give rise to all blood and immune cells in our body. Residing in the bone marrow (BM), HSCs are surrounded by numerous cell types and the associated extracellular matrix, which form a unique microenvironment known as ‘’HSC niche’’. Sympathetic neurons are important BM niche regulators, controlling HSC traffic in and out of the BM through the activation of β-adrenergic receptors (β-ARs). However, whether BM sympathetic-adrenergic signalling regulates other functions of HSCs remains poorly understood. Upon ageing, HSCs are functionally impaired, characterised by increased proliferation, decreased regenerative capacity, and myeloid/megakaryocytic-biased differentiation at the expense of lymphoid cell production. Ageing is associated with an increased risk to develop myeloid malignancies, but the contributions of HSC-intrinsic and -extrinsic ageing mechanisms remain debated. The current study aimed to understand how BM niches influence HSC fate in mouse models of ageing and age-related myeloid disorders, with a particular focus on microenvironmental regulation of myelopoiesis/megakaryopoiesis in response to neuronal inputs. During normal ageing, HSC niches decrease near bone but expand further from bone. Adrenergic signalling regulates lymphoid-myeloid balance during ageing. Whereas β2-AR promotes myeloid and megakaryocyte (Mk) differentiation through stromal-cell-derived interleukin-6 (IL-6), reduced β3-AR signalling accelerates ageing by remodelling HSC niches and diminishing lymphoid-biased HSCs. Similarly, non-HSC-autonomous premature haematopoietic ageing is observed in Hutchinson-Gilford progeria syndrome (HGPS). Chronic treatment of β3-AR agonist partially rejuvenates premature haematopoietic ageing in HGPS and restores exacerbated megakaryopoiesis in myeloproliferative neoplasms (MPNs). In summary, these results suggest that HSC niche remodelling and a functional switch of sympathetic activity (β2-AR overriding β3-AR) contribute to myeloid expansion during normal ageing. Certain ageing features in HGPS and aged-related pathological conditions could be improved by targeting the microenvironment.
Supervisor: Mendez-Ferrer, Simon Sponsor: University of Cambridge
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: ß-adrenergic receptors ; haematopoietic stem cell ageing ; HSC niche ; bone marrow microenvironment ; Hutchinson-Gilford progeria syndrome ; myeloproliferative neoplasms ; megakaryocyte