Discovery and characterisation of yolk-sac derived Endothelial-Macrophage progenitor cells in postnatal murine tissues
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(Thesis)
Date
2021
Authors
Williamson, Anna Emilie
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Psaltis, Peter
Bursill, Christina
Bonder, Claudine
Bursill, Christina
Bonder, Claudine
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Abstract
New blood vessel formation is central to many pathophysiological processes, such as atherosclerosis and cancer, and is closely intertwined with inflammation. Macrophages accumulate at sites of neovascularisation and support endothelial cells that line new blood vessels. It follows that a better understanding of how the intricate relationships between macrophages and endothelial cells come about, may open up new therapeutic opportunities to target these major disease processes. One important clue may lie in the ontogenies of both cell lineages, which increasingly appear to overlap, at least during early prenatal life. Converging lines of evidence indicate that macrophages and endothelial cells share a common ancestor, c-Kit+CSF1R+ erythromyeloid progenitors (EMP), which arise in extra-embryonic yolk sac (YS), as shown by murine lineage mapping studies. These recent observations align well with historical descriptions of bipotent haemangioblasts in YS and haemogenic endothelium in both the YS and aorta-gonad-mesonephros (AGM) during embryogenesis. Current expert consensus contends that YS-derived macrophages and endothelial cells are seeded in tissues prenatally and are maintained after birth by local self-renewal in their mature, differentiated state. However, an alternative, largely neglected explanation is that the YS also releases EMP-like progenitors to different tissues that persist postnatally to sustain local myeloid and endothelial populations under steady-state and mediates their expansion in disease. Using complementary experimental approaches, this thesis has uncovered for the first time the existence of clonogenic progenitor cells in postnatal murine tissues (aorta, heart, lung, skin, skeletal muscle), that express CD45, Sca-1, c-Kit, CX3CR1 and CSF1R and derive embryonically from early-wave YS EMPs. These tissue-resident progenitors have finite capacity for self-renewal, decreasing in prevalence with postnatal ageing (e.g. ~100 per 105 cells in neonatal aorta, ~55 at 3 weeks, ~15 at 12 weeks, ~5 at 52 weeks, p<0.01). Analysis of Flt3Cre x RosamT/mG mice demonstrated that these progenitors arise from a Flt3-ve source, indicating they are not derived or maintained from definitive haematopoiesis as occurs in postnatal bone marrow. Rather, embryonic profiling and tamoxifen-induced lineage mapping revealed that they arise in extra-embryonic yolk sac at E8.5 and are seeded in intra-embryonic tissues around E10.5, where they persist until after birth. Using in vitro and ex vivo differentiation studies, we have determined that these YS-derived CD45+/LoSca-1+c-Kit+CX3CR1+CSF1R+ progenitors are bipotent for both macrophages and endothelial cells, also possessing striking vasculogenic capacity. This was also confirmed in vivo by adoptive transfer into different murine models of disease or physiological conditions, including atherosclerosis, skin wound injury, melanoma and peripheral ischaemia, where progenitors achieved robust engraftment, proliferative expansion and generation of intact, perfused neovessels. We propose that these previously unidentified Endothelial-Macrophage (EndoMac) progenitor cells provide a local ancestral source for inflammatory and vasculogenic responses in postnatal tissues, and contribute to the apparent self-maintenance of YS-derived tissue-resident macrophages and endothelium after birth.
School/Discipline
Adelaide Medical School
Dissertation Note
Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2022
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