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Title: Endothelial colony-forming cells and transforming growth factor-β superfamily signalling in idiopathic pulmonary arterial hypertension
Author: Lao, Ka Hou
ISNI:       0000 0004 2736 9772
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Circulating endothelial progenitor cells may be important in the pathogenesis of idiopathic pulmonary arterial hypertension (IPAH) and give rise to endothelial colony-forming cells (ECFCs) in culture. These cells represent an accessible surrogate population to investigate endothelial dysfunction in IPAH. Peripheral blood mononuclear cells were cultured from healthy volunteers (n=25, 72% female; age range 23-57 yr) and IPAH patients (n=30, 60% female; age range 22-56 yr). Older IPAH patients (n=6, 50% female; age range 62-82 yr) were also sampled. Distinct colonies appeared after 13-35 days and exhibited a typical cobblestone morphology. The average frequency of colonies and clonal growth of isolated cells was similar in healthy volunteers and IPAH patients. Age-dependent differences were observed however in the number and frequency of colonies, which declines with age in the control but not in IPAH subjects. The endothelial phenotype was confirmed by immunostaining and flow cytometry, exhibiting endothelial and progenitor markers, but not hematopoietic markers. Endothelial cell functions, including proliferation, angiogenesis, migration and responses to apoptotic stimuli, were compared in cells between passages 4 to 7. IPAH cells showed enhanced angiogenic capacity (tube formation on Matrigel), significantly less apoptosis (lower caspase-3/7 activity) in response to serum and growth factor deprivation, and impaired migratory capacity compared with control ECFCs. Dysfunctional transforming growth factor (TGF)-β and bone morphogenetic protein receptor expression and signalling are implicated in IPAH and were assessed by RT-PCR and western blotting. IPAH and control ECFCs differed in their TGF-β type I (ALK5) receptor expression/signalling and in the expression of other regulatory proteins (e.g. chloride-like intracellular channel-4). Blood-derived ECFCs display an endothelial lineage similar to that of mature endothelial cells. ECFCs from IPAH patients have a distinct functional phenotype and exhibit differences in TGF-β receptor superfamily expression/signalling, which may contribute to endothelial dysfunction and vascular remodelling in IPAH.
Supervisor: Zhao, Lan ; Howard, Luke ; Wharton, John Sponsor: British Heart Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral