Human adipose-derived mesenchymal stem cells ameliorate Diabetic Kidney Disease by restoring macrophage efferocytosis

Diabetic Kidney Disease (DKD) is a major complication driven by chronic inflammation and impaired tissue homeostasis. While mesenchymal stem cells (MSCs) show promise, the precise mechanisms by which human adipose-derived MSCs (hASCs) modulate macrophage-mediated resolution of inflammation remain to be fully elucidated. We integrated single-cell RNA sequencing (scRNA-seq) analysis of human DKD kidneys with in vivo evaluations in db/db mice and in vitro co-culture models. We employed transcriptomic and molecular approaches to systematically investigate how hASCs impact macrophage functional states. scRNA-seq revealed a significant dysregulation of phagocytosis and efferocytosis pathways in human DKD macrophages. In vivo, hASCs effectively homed to injured kidneys, improved renal filtration, and attenuated pathological injury. Rather than a simple binary pro-inflammation to anti-inflammatory switch, hASC treatment restored a comprehensive efferocytic program involving multiple functional stages: chemotaxis (GPR132), recognition/engulfment (PARP9, ELMO1, RAC1), and lysosomal digestion/exhaution and polarisation (LAMP1, LIPA, PPAR-γ, ABCA1). This multi-targeted enhancement was accompanied contributed to the efficient clearance of apoptotic cells, reduced renal oxidative stress, and the mitigation of chronic inflammation. Our study systematically delineates the therapeutic benefits of hASCs, suggesting the promotion of macrophage efferocytosis as a significant mechanistic pathway by which hASCs exert their therapeutic effects. Specifically, we demonstrate that hASCs positively regulate key molecular signatures across multiple stages of this process — from “find-me” signal (LPC/GPR132) and “eat-me” recognition (PS/ELMO1) to lysosomal digestion (LAMP1) and subsequent exhaustion and polarisation (LIPA/PPAR-γ/ABCA1).