Metabolic Reprogramming of B Cells Can Be Reshaped by Mesenchymal Stem Cells in Ischemic AKI

Background: Lymphocytes are regulated by metabolic programming and play a role in repair after AKI. The mechanism by which mesenchymal stem cell (MSC)-based therapy enhances organ repair remains incompletely understood, as MSCs do not directly replace damaged tissue. Given that B cells contribute to kidney fibrosis and AKI-to-CKD transition, we hypothesized that 1. AKI induces B cell metabolic reprogramming, and 2. MSC therapy in AKI leads to metabolic rewiring of B cells. Methods: Moderate-to-severe ischemic AKI was induced by ischemia-reperfusion injury surgery in C57B/6 mice. Mice were treated with Wharton’s jelly MSC (WJ-MSC) or vehicle after AKI. Kidneys were collected at multiple time points, and lymphocytes were isolated and studied with a flow cytometry-based immune-metabolic assay. Results: B cells underwent metabolic reprogramming after AKI. In the early recovery phase, expression of enzymes related to glycolysis (normalized MFI, Sham vs. AKI, GLUT1 0.73±0.11 vs. 0.33±0.09, P=0.016; HKII 0.65±0.13 vs. 0.25±0.05, P=0.006) and mitochondrial oxidative phosphorylation (OXPHOS) (Tomm20 0.60±0.14 vs. 0.25±0.06, P=0.022) was downregulated. In the late recovery phase, B cells demonstrated a metabolic shift characterized by upregulation of fatty acid oxidation (FAO) (CPT1a 0.30±0.10 vs. 0.76±0.06, P=0.001) and mTOR activity (phospho-S6 0.24±0.09 vs 0.62±0.08, P=0.010). WJ-MSC treatment after AKI modulated these metabolic changes. In the early recovery phase, MSC treatment suppressed FAO (Vehicle vs. MSC, CPT1a 0.73±0.08 vs. 0.43±0.11, P=0.046) and OXPHOS machineries (VDAC1 0.65±0.10 vs. 0.30±0.11, P=0.037; Tomm20 0.58±0.12 vs. 0.21±0.06, P=0.044). In the late recovery phase, MSCs downregulated glycolysis (GLUT1 0.59±0.12 vs. 0.30±0.07, P=0.049; HKII 0.59±0.10 vs. 0.41±0.07, P=0.033) while further enhancing mTOR activity (phospho-S6 0.27±0.07 vs. 0.72±0.10, P=0.004). MSC treatment also induced broader lymphocyte changes, increasing the proportion of CD8+ T cells (22±2.4% vs. 30±2.4%, P=0.032) and decreasing CD4+ (69±2.8% vs. 61±1.9%, P=0.032) and NK T cells (1.10±0.11% vs. 0.73±0.05%, P=0.008). Conclusion: AKI inducedmetabolic reprogramming of kidney B cells. WJ-MSC treatment reshaped B cell metabolic profile and altered lymphocyte compositions, suggesting a potential mechanism by which MSC therapy promotes kidney repair following AKI.