News
Recent publications by RBK projects
Dec 11, 2023
We are thrilled to bring you the latest updates from our community of researchers who are making significant strides in kidney regeneration and related fields. Here are four recent publications that each represent a leap forward in our understanding and capabilities in kidney research.
In Vivo Assessment of Laboratory-Grown Kidney Tissue Grafts
Authors: Chuang, Tinghsien; Bejar, Justin; Yue, Zhiwei; Slavinsky, Mary; Marciano, Denise; Drummond, Iain and Oxburgh, Leif
Journal: Bioengineering (Basel). Vol. 10(11), 1261. October 2023.
URL: https://www.doi.org/10.3390/bioengineering10111261
Summary: We show that one significant obstacle to tubule fusion is the accumulation of fibrillar collagens at the interface between the graft and the host. As a screening strategy to identify factors that can prevent this collagen accumulation, we propose encapsulating laboratory-grown kidney tissue in fibrin hydrogels supplemented with candidate compounds such as recombinant proteins, small molecules, feeder cells, and gene therapy vectors to condition the local graft environment. We demonstrate that the AAV-DJ serotype is an efficient gene therapy vector for the subcapsular region and that it is specific for interstitial cells in this compartment. In addition to the histological evaluation of epithelial tubule fusion, we demonstrate the specificity of two urine biomarker assays that can be used to detect human-specific markers of the proximal nephron (CD59) and the distal nephron (uromodulin), and we demonstrate the deposition of human graft-derived urine into the mouse collecting system. Using the testing platform described in this report, it will be possible to systematically screen factors for their potential to promote epithelial fusion of graft and host tissue with a functional intravital read-out.
Navigating the kidney organoid: insights into assessment and enhancement of nephron function
Authors: Tabibzadeh, Nahid; Satlin, Lisa M.; Jain, Sanjay and Morizane, Ryuji
Journal: American Journal of Physiology-Renal Physiology. Vol. 325(6), F695–F706. December 2023.
URL: https://doi.org/10.1152/ajprenal.00166.2023
Summary: Kidney organoids are three-dimensional structures derived from stem cells, mimicking the major components of mammalian kidneys. Although they show great promise, their functional capacity has become a critical question. This review explores the advancements and challenges in evaluating and enhancing kidney organoid function, including the use of organ-on-chip technologies, multiomics data, and in vivo transplantation. Integrating these approaches to further enhance their physiological relevance will continue to advance disease modeling and regenerative medicine applications.
Uniform quantification of single-nucleus ATAC-seq data with Paired-Insertion Counting (PIC) and a model-based insertion rate estimator
Authors: Miao, Zhen and Kim, Junhyong
Journal: Nature Methods. December 2023.
URL: https://doi.org/10.1038/s41592-023-02103-7
Summary: Existing approaches to scoring single-nucleus assay for transposase-accessible chromatin with sequencing (snATAC-seq) feature matrices from sequencing reads are inconsistent, affecting downstream analyses and displaying artifacts. We show that, even with sparse single-cell data, quantitative counts are informative for estimating the regulatory state of a cell, which calls for a consistent treatment. We propose Paired-Insertion Counting as a uniform method for snATAC-seq feature characterization and provide a probability model for inferring latent insertion dynamics from snATAC-seq count matrices.
Stromal netrin 1 coordinates renal arteriogenesis and mural cell differentiation
Authors: Luo, Peter M. and Gu, Xiaowu and Chaney, Christopher and Carroll, Thomas and Cleaver, Ondine
Journal: Development
URL: https://doi.org/10.1242/dev.201884
Summary: The kidney vasculature has a complex architecture that is essential for renal function. The molecular mechanisms that direct development of kidney blood vessels are poorly characterized. We identified a regionally restricted, stroma-derived signaling molecule, netrin 1 (Ntn1), as a regulator of renal vascular patterning in mice. Stromal progenitor (SP)-specific ablation of Ntn1 (Ntn1SPKO) resulted in smaller kidneys with fewer glomeruli, as well as profound defects of the renal artery and transient blood flow disruption. Notably, Ntn1 ablation resulted in loss of arterial vascular smooth muscle cell (vSMC) coverage and in ectopic SMC deposition at the kidney surface. This was accompanied by dramatic reduction of arterial tree branching that perdured postnatally. Transcriptomic analysis of Ntn1SPKO kidneys revealed dysregulation of vSMC differentiation, including downregulation of Klf4, which we find expressed in a subset of SPs. Stromal Klf4 deletion similarly resulted in decreased smooth muscle coverage and arterial branching without, however, the disruption of renal artery patterning and perfusion seen in Ntn1SPKO. These data suggest a stromal Ntn1-Klf4 axis that regulates stromal differentiation and reinforces stromal-derived smooth muscle as a key regulator of renal blood vessel formation.
