Collateral arteries act as natural bypasses which re-route blood flow to ischemic regions and facilitate tissue regeneration. In an injured heart, neonatal artery endothelial cells orchestrate a systematic series of cellular events, which includes their outward migration, proliferation, and coalescence into fully functional collateral arteries. This process, called Artery Reassembly, aids complete cardiac regeneration in neonatal hearts, but is absent in adults. The reason for this age-dependent disparity in artery cell response is completely unknown. In this study, we investigated if regenerative potential of coronary arteries, like in cardiomyocytes, is dictated by their ability to de-differentiate. We performed single cell RNA sequencing of coronary endothelial cells and identified differences in molecular profiles of neonatal and adult endothelial cells. Neonates show significant increase in actively cycling artery cells that expressed prominent de-differentiation markers. Using both, in silico pathway analyses and in vivo experiments, we show that cell cycle re-entry of pre-existing artery cells, subsequent collateral artery formation and cardiac function is dependent on arterial VegfR2. This sub-population of de-differentiated and proliferating artery cells is absent in non-regenerative P7 or adult hearts. Together, our data indicate that adult artery endothelial cells fail to drive collateral artery development due to their limited ability to de-differentiate and proliferate.

De-differentiation and Proliferation of Artery Endothelial Cells Drive Coronary Collateral Development

Extracellular vesicles (EVs) secreted by stem and progenitor cells have significant potential as cell-free ‘cellular’ therapeutics. Yet, small EVs (<200 nm) are rapidly cleared after systemic administration, mainly by the liver, presenting challenges targeting EVs to a specific organ or tissue. Microencapsulation using natural nano-porous hydrogels (microgels) has been shown to enhance engraftment and increase the survival of transplanted cells. We sought to encapsulate EVs within microgels to target their delivery to the lung by virtue of their size-based retention within the pulmonary microcirculation. Mesenchymal stromal cell (MSC) derived EVs were labelled with the lipophilic dye (DiR) and encapsulated within agarose-gelatin microgels. Endothelial cells and bone marrow derived macrophages were able to take up EVs encapsulated in microgels in vitro, but less efficiently than the uptake of free EVs. Following intrajugular administration, microgel encapsulated EVs were selectively retained within the lungs for 72 hours, while free EVs were rapidly cleared by the liver. Furthermore, microgel loaded EVs demonstrated greater uptake by lung cells, in particular CD45+ immune cells, as assessed by flow cytometry compared to free EVs. Microencapsulation of EVs may be a novel tool for enhancing targeted delivery of EVs for future therapeutic applications.

Targeting extracellular vesicle delivery to the lungs by microgel encapsulation

Collateral arteries act as natural bypasses which reroute blood flow to ischemic regions and facilitate tissue regeneration. In an injured heart, neonatal artery endothelial cells orchestrate a systematic series of cellular events, which includes their outward migration, proliferation, and coalescence into fully functional collateral arteries. This process, called artery reassembly, aids complete cardiac regeneration in neonatal hearts but is absent in adults. The reason for this age-dependent disparity in artery cell response is completely unknown. In this study, we investigated if regenerative potential of coronary arteries is dictated by their ability to dedifferentiate.Single-cell RNA sequencing of coronary endothelial cells was performed to identify differences in molecular profiles of neonatal and adult endothelial cells in mice. Findings from this in silico analyses were confirmed with in vivo experiments using genetic lineage tracing, whole organ immunostaining, confocal imaging, and cardiac functional assays in mice.Upon coronary occlusion, neonates showed a significant increase in actively cycling artery cells and expressed prominent dedifferentiation markers. Data from in silico pathway analyses and in vivo experiments suggested that upon myocardial infarction, cell cycle reentry of preexisting neonatal artery cells, the subsequent collateral artery formation, and recovery of cardiac function are dependent on arterial VegfR2 (vascular endothelial growth factor receptor-2). This subpopulation of dedifferentiated and proliferating artery cells was absent in nonregenerative postnatal day 7 or adult hearts.These data indicate that adult artery endothelial cells fail to drive collateral artery development due to their limited ability to dedifferentiate and proliferate. 

https://www.ahajournals.org/doi/pdf/10.1161/ATVBAHA.123.319319

Dedifferentiation and Proliferation of Artery Endothelial Cells Drive Coronary Collateral Development in Mice

Lung regeneration deteriorates with aging leading to increased susceptibility to pathologic conditions, including fibrosis. Here, we investigated bleomycin-induced lung injury responses in young and aged mice at single-cell resolution to gain insights into the cellular and molecular contributions of aging to fibrosis. Analysis of 52,542 cells in young (8 weeks) and aged (72 weeks) mice identified 15 cellular clusters, many of which exhibited distinct injury responses that associated with age. We identified Pdgfra+ alveolar fibroblasts as a major source of collagen expression following bleomycin challenge, with those from aged lungs exhibiting a more persistent activation compared to young ones. We also observed age-associated transcriptional abnormalities affecting lung progenitor cells, including ATII pneumocytes and general capillary (gCap) endothelial cells (ECs). Transcriptional analysis combined with lineage tracing identified a sub-population of gCap ECs marked by the expression of Tropomyosin Receptor Kinase B (TrkB) that appeared in bleomycin-injured lungs and accumulated with aging. This newly emerged TrkB+ EC population expressed common gCap EC markers but also exhibited a distinct gene expression signature associated with aberrant YAP/TAZ signaling, mitochondrial dysfunction, and hypoxia. Finally, we defined ACKR1+ venous ECs that exclusively emerged in injured lungs of aged animals and were closely associated with areas of collagen deposition and inflammation. Immunostaining and FACS analysis of human IPF lungs demonstrated that ACKR1+ venous ECs were dominant cells within the fibrotic regions and accumulated in areas of myofibroblast aggregation. Together, these data provide high-resolution insights into the impact of aging on lung cell adaptability to injury responses.

/pdf/single-cell-transcriptomics-of-fibrotic-lungs-unveils-aging-3qjpnn1s.pdf

Single Cell Transcriptomics of Fibrotic Lungs Unveils Aging-associated Alterations in Endothelial and Epithelial Cell Regeneration

S100A6 as a Constituent and Potential Marker of Adult and Cancer Stem Cells

Rational: Endothelial damage plays a central role in acute lung injury, and regeneration of lung vascular endothelium is required for its resolution in preclinical models. Objectives: We sought to define the cellular and molecular mechanisms underlying lung microvascular regeneration in acute lung injury induced by lung endothelial cell ablation. Methods: Transgenic mice were created expressing endothelial-targeted human diphtheria toxin receptor. Changes in lung cell populations and gene expression profiles were determined using single-cell RNA sequencing of dissociated lung cells (10x Genomics) at baseline (day 0) and days 3, 5 and 7 days after lung endothelial cell ablation. Measurements and Main Results: Intratracheal instillation of diphtheria toxin resulted in ablation of ~70% of lung endothelial cells, producing severe acute lung injury, with complete resolution by 7 days. Single cell analysis revealed 8 distinct endothelial cell clusters, including type-A capillary endothelial cells which were characterized by the unique expression of apelin at baseline. Diphtheria toxin-induced ablation resulted in the emergence of novel stem-like endothelial cells in the transitional 9general9 capillary type-B endothelial population at day 3, characterized by the de novo expression of apelin. This was followed by the appearance of proliferative endothelial cells at day 5 expressing apelin receptor and Forkhead box M1 which were responsible for replenishment of all depleted endothelial cell populations. Treatment with an apelin receptor antagonist prevented recovery post DT resulting in excessive mortality. Conclusions: Targeted endothelial cell ablation revealed a remarkable regenerative capacity of the lung microvasculature orchestrated by newly emergent apelin-expressing endothelial stem-like cells primed for endothelial repair.

https://biorxiv.org/content/10.1101/2021.07.12.452061v1.full.pdf

Newly Emergent Apelin Expressing Endothelial Stem-like Cells Orchestrate Lung Microvascular Repair

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Newly Emergent Apelin Expressing Endothelial Stem-like Cells Orchestrate Lung Microvascular Repair