Integrating spatial transcriptomics with single-cell transcriptomics reveals a spatiotemporal gene landscape of the human developing kidney

Abstract

Background Research on spatiotemporal gene landscape can provide insights into the spatial characteristics of human kidney development and facilitate kidney organoid cultivation. Here, we profiled the spatiotemporal gene programs of the human embryonic kidneys at 9 and 18 post-conception weeks (PCW) by integrating the application of microarray-based spatial transcriptomics and single-cell transcriptomics. Results We mapped transcriptomic signatures of scRNA-seq cell types upon the 9 and 18 PCW kidney sections based on cell-type deconvolution and multimodal intersection analyses, depicting a spatial landscape of developing cell subpopulations. We established the gene characteristics in the medullary regions and revealed a strong mitochondrial oxidative phosphorylation and glycolysis activity in the deeper medullary region. We also built a regulatory network centered on GDNF-ETV4 for nephrogenic niche development based on the weighted gene co-expression network analysis and highlighted the key roles of Wnt, FGF, and JAG1-Notch2 signaling in maintaining renal branching morphogenesis. Conclusions Our findings obtained by this spatiotemporal gene program are expected to improve the current understanding of kidney development.

Spatial Transcriptomics: A Powerful Tool in Disease Understanding and Drug Discovery

“…Therefore, studying human organ development through organoids in vitro offers a higher level of fidelity compared to that of model organisms such as mice or cell-based models 155 . From another perspective, gaining an understanding of organ development patterns in human embryos is also advantageous for the cultivation of organoids 156 . The application of scRNA-seq in developmental biology enables the comprehensive analysis of tissue transcriptomes at single-cell resolution across various stages of development 157 , 158 .…”

“…Legnini et al devised a method for spatiotemporally programming organoids to establish unique gene expression domains, validated this approach using ST, and revealed the role of the SHH pathway in an organoid model of human neurodevelopment 170 . In the study of kidney development, spatial and temporal transcriptomic analysis of human embryonic kidneys has been employed to elucidate intercellular signalling during organoid development and the key factors that regulate kidney development, thus facilitating the cultivation of kidney organoids 156 .…”

Challenges and Opportunities for the Clinical Translation of Spatial Transcriptomics Technologies

“…These atlases define the spatial and functional organization of the kidney, altered/injured epithelial cells states and their niches, as well as the associated responses by immune cells. Additional studies using 10x Genomics Visium on human kidney tissues have provided insights into kidney development [ 34 ], angiogenesis, and inflammation in diabetic kidney disease [ 35 , 36 ], roles for innate immune cells in allograft rejection [ 37 ], epithelial cell-immune cell crosstalk in acute kidney injury [ 38 ], and remodeling mechanisms in the medulla in response to nephrolithiasis [ 39 ]. Investigators have also applied this powerful technology to study mouse models of ischemia reperfusion kidney injury [ 38 , 40 , 41 ] and chronic kidney disease induced by aristolochic acid [ 42 ].…”

Single cell RNA‐sequencing: A powerful yet still challenging technology to study cellular heterogeneity

“…[87][88][89][90][91] In instances where location is crucial to infer intercellular communication, for example to study the infiltration of immune cells in hot versus cold tumours, spatial transcriptomics provides the additional dimension to decipher the puzzle. [92] However, due to the complexity of preserving spatial information, spatial transcriptomics technologies are costlier and have lower sequencing depth, resolution, and accessibility compared to scRNA-seq. [13,[93][94][95] Hence, they are usually used to identify a predefined panel of markers.…”