A new study featured in Nature Communications sheds light on how damaged cells behave in harmful environments following acute kidney injury (AKI). Due to limited treatment choices, AKI often leads to chronic kidney disease (CKD), which impacts more than 1 in 7 adults in the U.S., amounting to around 37 million individuals.
The insights gained could aid future strategies to hinder the onset of CKD, potentially preventing kidney failure.
This research was a collaborative effort involving scientists from Andy McMahon’s lab at USC and Long Cai’s lab at Caltech, backed by a USC Broad Innovation Award that facilitated this cross-institutional project.
In this research, co-first authors Michal Polonsky from Caltech and Louisa Gerhardt from USC utilized an advanced technique named seqFISH, created in the Cai lab. This innovative approach enabled them to collect data on gene activity and examine cell interactions in intact kidney tissues from mice experiencing AKI. With this technology, researchers were able to analyze the detailed expression of over 1,000 genes in the damaged kidney tissues, pinpoint microenvironments linked to injury, and forecast the cell interactions related to the advancement to CKD.
“Dr. Cai’s seqFISH technology gives us unmatched insights into the cellular dynamics in the kidney post-injury,” stated McMahon, who serves as the W.M. Keck Provost and University Professor of Stem Cell Biology and Regenerative Medicine at USC before joining Caltech’s faculty in October. “A clearer understanding of kidney damage is essential for identifying prevention targets against chronic kidney disease.”
Cai, a Professor of Biology and Biological Engineering, expressed: “We are excited that our technology has led to a deeper comprehension of kidney injury and illness. This study emphasizes the significance of cross-institutional and interdisciplinary collaborations in advancing biomedical research.”
The researchers discovered a likely pathogenic microenvironment in the outer layer of the kidney, which they termed “ME-5.” This region was characterized by a specific kidney cell type known as proximal tubule cells (PTs), which are particularly susceptible to injury.
Within ME-5, injured PTs and neighboring connective tissue cells called fibroblasts exchanged signals that might exacerbate injury. Critical signals involved genes Clcf1 and Crfl1, which produce proteins that could encourage inflammation and fibrosis (scarring). Other signals found in ME-5 might promote the recruitment of immune cells, thereby fueling further inflammation, scarring, and other harmful changes.
The researchers also identified another significant injury-related microenvironment, named “ME-16,” which featured clusters of various immune cell types known as tertiary lymphoid structures, recognized for their role in chronic inflammation. Unlike being confined to a single area, ME-16 was widespread across the injured kidney.
To disseminate their findings, the team developed a thorough map of both cellular and structural alterations occurring after AKI, enhancing our understanding of the shift towards CKD. This map can be accessed publicly at https://woldlab.caltech.edu/ci2-celltiles/Mouse-Kidney-Fibrosis/.
Additional contributors include Kari Koppitch from USC; Jina Yun, Katsuya Lex Colón, Henry Amrhein, Matt Thomson, and Barbara Wold from Caltech; as well as Shiwei Zheng and Guo-Cheng Yuan from the Icahn School of Medicine at Mount Sinai.
Besides the support from the USC Broad Innovation Award, the study was financed by the National Institutes of Health (grant NIDDK UC2DK126024), the German Research Foundation (grant GE 3179/1-1), and the German Society of Internal Medicine (DGIM) Clinician Scientist Grant.
Disclosures: Cai is a co-founder of Spatial Genomics, Inc., while McMahon serves as a consultant to eGENESIS, Trestle Biotherapeutics, IVVA Medical, and GentiBIO.
