Deciphering Endothelial and Mesenchymal Organ Specification in Vascularized Lung and Intestinal Organoids

Miao, Yifei; Tan, Cheng; Pek, Nicole M.; Yu, Zhiyun; Iwasawa, Kentaro; Kechele, Daniel O.; Sundaram, Nambirajan; Pastrana-Gomez, Victor; Kishimoto, Keishi; Yang, Min-Chi; Jiang, Cheng; Tchieu, Jason; Whitsett, Jeffrey A.; McCracken, Kyle W.; Rottier, Robbert J.; Kotton, Darrell N.; Helmrath, Michael A.; Wells, James M.; Takebe, Takanori; Zorn, Aaron M.; Chen, Ya-Wen; Guo, Minzhe; Gu, Mingxia

doi:10.1101/2024.02.06.577460

Cited by 2 publications

References 83 publications

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AMEF2Ctranscription factor network regulates proliferation of glomerular endothelial cells in diabetic kidney disease

Ferreira,

Gisch,

Phillips

et al. 2024

Preprint

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Background: The maintenance of a healthy epithelial-endothelial juxtaposition requires cross-talk within glomerular cellular niches. Neovascularization and nodular mesangial sclerosis are manifestations of dysregulated communication in diabetic kidney disease (DKD). We sought to understand the spatially-anchored regulation and transition of endothelial and mesangial cells from health to injury in DKD. Methods: From 77 human kidney biopsy samples, an integrated multi-omics approach was leveraged to identify cellular niches, cell-cell communication, cell injury trajectories, and regulatory transcription factor (TF) networks in glomerular endothelial and mesangial cells. Data were culled from single nucleus RNA sequencing, single nucleus ATAC sequencing, and three orthogonal spatial transcriptomic technologies. Molecular information was correlated with histopathological manifestations of DKD and queried in a human clinical trial dataset. Results: We identified a cellular niche of the diabetic glomerulus enriched in a proliferative endothelial cell sub type (prEC) and altered vascular smooth muscle cells (VSMCs). Cellular communication within this niche maintained pro-angiogenic signaling with loss of anti-angiogenic factors. We identified a TF network of MEF2C, MEF2A, and TRPS1 which regulated SEMA6A and PLXNA2, a receptor-ligand pair opposing angiogenesis. In silico knockout of the TF network led to disruption of the transition from a healthy glomerular capillary endothelial cell (EC-GC) to a prEC, with concomitant acceleration toward a degenerative (injury) endothelial phenotype. Glomeruli enriched in the prEC niche had histologic evidence of neovascularization and a second pro-fibrotic niche mapped in segmentally sclerotic DKD glomeruli. MEF2C activity was increased in diabetic glomeruli and more so in glomeruli with nodular mesangial sclerosis. The gene regulatory network (GRN) of MEF2C was dysregulated in EC-GCs of patients with DKD, but sodium glucose trasporter-2 inhibitor (SGLT2i) treatment reversed the MEF2C GRN effects of DKD. Conclusions: The MEF2C, MEF2A, and TRPS1 TF network carefully balances the fate of the EC-GC in DKD. When the TF network is 'on' or over-expressed in DKD, an EC-GC may progress to a prEC state. When the TF network is off, the EC-GC progresses toward a cell death state. prEC abundance and signaling underlie neovascularization in DKD. SGLT2i therapy restores the balance of MEF2C activity in DKD.

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AMEF2Ctranscription factor network regulates proliferation of glomerular endothelial cells in diabetic kidney disease

Ferreira,

Gisch,

Phillips

et al. 2024

Preprint

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Generation of vascularized pancreatic progenitors through co-differentiation of endoderm and mesoderm from human pluripotent stem cells

Sang,

Xu,

Wang

et al. 2024

Stem Cell Res Ther

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Background The simultaneous differentiation of human pluripotent stem cells (hPSCs) into both endodermal and mesodermal lineages is crucial for developing complex, vascularized tissues, yet poses significant challenges. This study explores a method for co-differentiation of mesoderm and endoderm, and their subsequent differentiation into pancreatic progenitors (PP) with endothelial cells (EC). Methods Two hPSC lines were utilized. By manipulating WNT signaling, we optimized co-differentiation protocols of mesoderm and endoderm through adjusting the concentrations of CHIR99021 and mTeSR1. Subsequently, mesoderm and endoderm were differentiated into vascularized pancreatic progenitors (vPP) by adding VEGFA. The differentiation characteristics and potential of vPPs were analyzed via transcriptome sequencing and functional assays. Results A low-dose CHIR99021 in combination with mTeSR1 yielded approximately 30% mesodermal and 70% endodermal cells. Introduction of VEGFA significantly enhanced EC differentiation without compromising PP formation, increasing the EC proportion to 13.9%. Transcriptomic analyses confirmed the effectiveness of our protocol, showing up-regulation of mesodermal and endothelial markers, alongside enhanced metabolic pathways. Functional assays demonstrated that vPPs could efficiently differentiate into insulin-producing β-cells, as evidenced by increased expression of β-cell markers and insulin secretion. Conclusion Our findings provide a robust method for generating vPPs, which holds significant promise for regenerative medicine applications, particularly in diabetes treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-024-04120-5.

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Deciphering Endothelial and Mesenchymal Organ Specification in Vascularized Lung and Intestinal Organoids

Cited by 2 publications

References 83 publications

AMEF2Ctranscription factor network regulates proliferation of glomerular endothelial cells in diabetic kidney disease

AMEF2Ctranscription factor network regulates proliferation of glomerular endothelial cells in diabetic kidney disease

Generation of vascularized pancreatic progenitors through co-differentiation of endoderm and mesoderm from human pluripotent stem cells

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