Thursday, May 2, 2024
5/2/2024
SUMMARY: Trisomy 21 (T21) is the most prevalent chromosomal abnormality worldwide, resulting in Down Syndrome (DS) [1, 2], a multisystem syndrome associated with cardiopulmonary disorders. Pulmonary disorders include pulmonary hypertension, pulmonary hypoplasia, pulmonary hemosiderosis and pulmonary capillaritis, all of which can result from a dysregulated lung endothelium. In addition, T21 lungs are characterized by the persistence of an immature double capillary network system surrounding the alveoli and representative of the saccular stage of development [3]. This suggests that endothelial defects in individuals with DS are likely initiated in utero. Single cell transcriptomics data demonstrated the presence of diverse endothelial cell populations in the human adult lung [4, 5]. While others and we have reported impaired endothelial networks in the developing T21 lung characterized by congested capillaries, lymphatic dilatation, and muscularized arteries [6], the nature of these defects and the different endothelial cell populations contributing to such defects are yet to be understood. Moreover, developing T21 human lungs display increased expression of anti-angiogenic factors [3, 6-8]. A decrease in endothelial progenitor cells is found in T21 peripheral blood [9]. Furthermore, T21 iPSC- derived endothelial cells exhibit decreased cell proliferation, impaired sprouting and tube formation compared to euploid cells [10]. One of the major pathways consistently activated in DS is the type I interferon (IFN) pathway [6]. Elevated type I IFN causes a decrease of endothelial progenitor cells [9] and inhibits VEGF induced development of capillary like structures [11, 12], thus playing an anti-angiogenic role. Additionally, type I interferonopathies are linked to pulmonary hypertension and pulmonary vasculopathy [13]. Sc-RNAseq data of T21 and euploid lung cells demonstrated the presence of several endothelial cell populations displaying increased expression of type I IFN signaling pathway genes in T21. Therefore, we hypothesize that defective lung angiogenesis occurs in T21 during development and is a result of type I IFN-dependent changes in endothelial cell proliferation, differentiation and migration. To test this hypothesis, we will 1) determine endothelial cell defects in T21 vs euploid human developing lungs by defining the different endothelial cell populations and their spatiotemporal distribution using combinatorial in situ hyridization with IF stainings and assessing defects in endothelial cell proliferation and sprouting of each group via IF and 3D image quantifications and 2) define the role of type I IFN signaling in the endothelial defects in T21 by determining the effect of gain and loss of type I IFN signaling on proliferation, migration, permeability and tube formation in primary and iPSC-derived endothelial cell cultures of T21 and euploid cells. Improved strategies to prevent, ameliorate or reverse endothelial related lung disease in DS will be contingent upon a detailed understanding of the defects and pathways driving these defects that may identify novel therapeutic targets for intervention.
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