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Generation of the organotypic kidney by integrating pluripotent stem cell-derived renal stroma

ABSTRACT: Organs consist of not only parenchyma but also stroma, the latter of which coordinates generation of organotypic structures. Despite recent advances in organoid technology, induction of organ-specific stroma and recapitulating the complex organ configurations from pluripotent stem cells (PSCs) has remained challenging. For the kidney, the stromal progenitor coordinates differentiation of the two parenchymal progenitors: nephron progenitor and ureteric bud. By identifying the origin and dorsoventral patterning of the renal stromal progenitor, we established its induction protocol from mouse PSCs. When the three types of progenitors were differentially induced from PSCs and assembled, the all PSC-derived organoids reproduced the complex kidney structures, with multiple types of stromal cells distributed around differentiating nephrons and branching ureteric buds. Thus, integration of PSC-derived stroma into the conventional organoids enables recapitulation of organotypic architecture.

ORGANISM(S): Mus musculus

PROVIDER: GSE178263 | GEO | 2021/12/05

REPOSITORIES: GEO

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Project description:During embryonic development, the first hematopoietic stem cells (HSCs) arise from a transient population of endothelial cells lining the ventral surface of the dorsal aorta, via a process of endothelial to hematopoietic transition (EHT) at embryonic day (E) 10.5. This region contains resident PDGFRA+ stromal cells (PSCs), but their identity and role in HSC generation in the AGM are not well understood. Using a library of compound transgenic mice, we identified a population of PDGFRA+/Nestin-GFP (N-GFP)-/PDGFRB-/CD31- cells with PSC activity in the E10.5 and E11.5 mouse AGM. Freshly isolated PSCs were adept at forming blood vessels with CD31+ luminal endothelium enveloped by PDGFRB+ pericytes, when transplanted subcutaneously into mice. Conditional ablation of PDGFRA+ or Nestin+ cells led to either complete or partial loss of PSCs respectively, with severe loss of endothelial and pericyte-like cells, and concomitant loss of blood formation in the AGM. Lineage tracing studies using tamoxifen induction in PDGFRACreERT2/R26eYFP embryos showed that stromal, sub-endothelial, endothelial and long-term repopulating hematopoietic stem cells (LT-HSCs) cells in the E11.5 AGM were progeny of PDGFRA cells. Using transgenic reporter mice, we showed that MesP1 (mesoderm) derived PDGFRA+ cells dominated the sub-endothelial and deeper ventral stroma in the AGM at E10.5 and E11.5 but were replaced by Wnt1 (neural crest) derived cells at E13.5. Re-aggregation of E11.5 Mesp1 derived PSC cells with E13.5 aortic or adult cardiac non-hemogenic endothelial cells resulted in the generation of endothelial cell derived LT-HSCs. RNA-sequencing analysis of non-hemogenic E13.5 endothelial cells showed up-regulation of EHT genes, WNT, BMP and Notch cell signalling pathways when re-aggregated with E11.5 Mesp1 derived PSCs. LT-HSC generation from these re-aggregates was suppressed by dose-dependent inhibition of PDGF-AA/PDGFRA signalling. Taken together, we report that PSC populations in the AGM are temporally dynamic, and that MesP1-derived PSCs regulate hemogenic potential of the endothelium and that this cooperativity is dependent on PDGF-AA/PDGFRA signalling. This submission represents the RNAseq component of the study.

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Generation of the organotypic kidney by integrating pluripotent stem cell-derived renal stroma

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