Transplantation of Ex Vivo Expanded Lrig1+ Cells Restores Kidney Function After Injury

Background: Without timely and targeted intervention, these conditions frequently progress to chronic kidney disease (CKD) or end-stage renal disease (ESRD), significantly reducing the window for successful treatment. Therefore, regenerative approaches utilizing cells with strong reparative capacities are urgently required, highlighting the critical need to identify reliable markers defining regenerative cell populations in the adult kidney. Previously, we identified Lrig1 as a novel marker for a rare population of long-lived, injury-responsive cells predominantly expressed in the proximal tubule (PT), where it supports PT homeostasis. Lineage-tracing revealed that Lrig1+ cells persist after acute injury, actively contribute to regeneration, and possess stem cell niche-like gene expression profiles, indicating their therapeutic potential in renal regeneration. Methods: To evaluate the therapeutic efficacy of Lrig1+ cells in vivo, acute kidney injury was induced in C57BL/6J mice via a single intraperitoneal injection of high-dose folic acid (250 mg/kg). Three days post-injury, Lrig1+ cell-derived renal organoids were transplanted via intrarenal injection. Renal tissues were harvested and analyzed 15 days after transplantation to assess structural and functional recovery. Results: To assess their regenerative capability, Lrig1+ cells were isolated from adult mouse kidneys and expanded ex vivo. While freshly isolated Lrig1+ cells initially showed proliferation and expansion capacities comparable to those of Lrig1− cells, prolonged culture allowed Lrig1+ cells to acquire stem-like properties, including sustained proliferation and the capacity to form organoids. Notably, these long-term cultured Lrig1+ cells displayed superior regenerative potential compared to other tubular cell populations. Renal organoids derived from expanded Lrig1+ cells were transplanted into AKI mouse models, where they successfully engrafted into damaged tubules and promoted significant structural and functional recovery. In direct comparison, Lrig1+ cells outperformed Lgr5+ stem cells isolated at postnatal day 7, which conferred only minimal histological improvement upon transplantation Conclusion: Collectively, these findings highlight Lrig1+ cells as a promising, expandable cell source for therapeutic kidney regeneration. Funding: Government Support – Non-U.S.