Early intervention with mesenchymal stem cells prevents nephropathy in diabetic rats by ameliorating the inflammatory microenvironment

Abstract

Diabetic nephropathy (DN) is a major complication of diabetes and represents the leading cause of end-stage renal disease. Mesenchymal stem cell (MSC) treatment has been demonstrated to be effective in DN models by reducing albuminuria and attenuating glomerular injury; however, limited in-depth understanding of the underlying mechanism and a lack of clinical trials hinders its clinical use. Additionally, most of these experimental studies were conducted on the advanced stage of nephropathy, which is difficult to reverse and consequently showed limited therapeutic efficacy. We sought to evaluate whether early intervention by MSCs has the potential to prevent DN onset and progression as well as protect kidney function when intravenously administered to rats with diabetes. Diabetes was induced in adult male SD rats by streptozotocin (STZ) injection (55 mg/kg, i.p.). The diabetic rats were injected with or without bone marrow-derived MSCs (5×106 per rat), via tail vein at 2, 4, 5 and 7 weeks after diabetes onset. Fasting blood glucose (FBG), blood urea nitrogen (BUN) and serum creatinine (Scr) levels in serum samples and glycosuria (GLU), microalbumin (MAU), and albumin to creatinine ratio (ACR) in urine samples were determined. Renal pathology and immunohistochemistry (IHC) for CD68, MCP-1, fibronectin (FN), transforming growth factor-β (TGF-β) and pro-inflammatory cytokines were also performed. Expression levels of the above factors as well as interleukin-10 (IL-10), and epidermal growth factor (EGF) were assessed by qPCR and multiplex bead-based suspension array system, respectively. Additionally, MSC tracing in vivo was performed. Ex vivo, peritoneal macrophages were co-cultured with MSCs, and expression of inflammatory cytokines was detected as well. MSC treatment profoundly suppressed renal macrophage infiltration and inflammatory cytokine secretion in diabetic rats, resulting in prominently improved kidney histology, systemic homeostasis, and animal survival, although no significant effect on hyperglycemia was observed. Engrafted MSCs were primarily localized in deteriorated areas of the kidney and immune organs 48 h after infusion. MSC treatment upregulated serum anti-inflammatory cytokines IL-10 and EGF. Ex vivo, MSCs inhibited lipopolysaccharide (LPS)-stimulated rat peritoneal macrophage activation via the downregulation of inflammatory-related cytokines such as IL-6, MCP-1, tumor necrosis factor-α (TNF-α) and IL-1β. Our results demonstrated that early intervention with MSCs prevented renal injury via immune regulation in diabetic rats, which restored the homeostasis of the immune microenvironment, contributing to the prevention of kidney dysfunction and glomerulosclerosis.

Human umbilical cord MSC‑derived hepatocyte growth factor enhances autophagy in AOPP‑treated HK‑2 cells

“…Furthermore, MSCs were demonstrated to increase α-synuclein removal in Parkinson's disease by increasing autophagy (25). In addition, Li et al (26) demonstrated that early intervention with MSCs prevented renal injury by ameliorating the inflammatory microenvironment in diabetic rats and Tang et al (27) reported that MSCs alleviate acute renal injury by suppressing the C5a/C5a anaphylatoxin chemotactic receptor-NF-κB signaling pathway. The results of the present study suggested that hUC-MSCs enhanced HK-2 cell autophagy and inhibited the PI3K/AKT/mTOR signaling pathway, which demonstrated a protective role of hUC-MSC in the aforementioned studies.…”

The Use of Pulsed Electromagnetic Field to Modulate Inflammation and Improve Tissue Regeneration: A Review

“…In particular, lipopolysaccharide (LPS)-stimulated macrophages produced more IL-10 when cultured with bone-marrow MSCs; however, this effect was eliminated if the bone-marrow MSCs lacked the genes encoding TLR-4, myeloid differentiation primary response gene-88, tumor necrosis factor-a (TNF-a), or Cox-2, 37 and in diabetic rats, MSC treatment upregulated anti-inflammatory cytokine IL-10. 38 MSCs appear to play a dual role whereby they promote the M1 differentiation of naive M F , yet in the presence of M1, MSCs promote the M1 to M2 conversion in MSC-M1 cocultures. 39 The differentiation of specific MSC/ M F cell phenotypes is closely related to the surrounding environment that acts as an orchestrator of immune activity.…”

Mesenchymal Stem Cells Transplantation in Diabetic Kidney Diseases: A Systematic Review and Meta-analysis

“…Lang et al reported 6 deaths of model rats during the construction of diabetes model [22] while Wang et al reported 1 death in both MSCs-treated group and DN group besides 2 deaths because of anesthesia [16]. In the study of Li et al, there was 1 rats dead in the DN group and 2 in the MSCs-treated group [27]. During a 12-…”

“…Glucose was almost detected after the MSCs treatment, except for 2 studies [27,32]. Sixteen studies measured glucose for once at the end of the experiment [13-16, 18-24, 26, 28-31].…”

“…The in ltration of renal macrophages and the expression of in ammatory cytokines were effectively inhibited by early intervention of MSCs in DM rats through the immune regulation and paracrine secretion of renal protective factors, restoring the homeostasis of immune microenvironment [27]. The failure of in ammatory regression may matter DM and its complications, and BM-MSCs could block the exacerbation of DKD through the LXA4-ALX/FPR2 axis to inhibit glomerulosclerosis and secretion of proin ammatory cytokines [28].…”