Diabetic microenvironment preconditioning of adipose tissue-derived mesenchymal stem cells enhances their anti-diabetic, anti-long-term complications, and anti-inflammatory effects in type 2 diabetic rats

Abstract

Background Mesenchymal stem cells (MSCs) exert anti-diabetic effects and improve long-term complications via secretory effects that regulate macrophage polarisation and attenuate inflammation. Enhancing the efficacy of MSCs needs to be explored further. The in vitro culture microenvironment influences the secretory profile of MSCs. Therefore, we hypothesised that a diabetic microenvironment would promote the secretion of cytokines responsible for macrophage polarisation, further attenuating systemic inflammation and enhancing the effects of MSCs on type 2 diabetes (T2D) and long-term diabetic complications. Methods Preconditioned adipose-derived mesenchymal stem cells (pre-ADSCs) were obtained after co-cultivating ADSCs in a diabetic metabolic environment (including high sugar, advanced glycation end-product, and lipopolysaccharides). The regulatory effects of pre-ADSCs on macrophages were observed in vitro. A T2D rat model was induced with a high-fat diet for 32 weeks combined with an intraperitoneal injection of streptozotocin. Sprague–Dawley (SD) rats were divided into four groups: normal group, diabetes without treatment group (PBS), ADSC treatment group, and pre-ADSC treatment group. ADSCs and pre-ADSCs were intravenously administered weekly to SD rats for 6 months, and then glucose homeostasis and long-term diabetic complications were evaluated in each group. Results The secretion of cytokines related to M2 macrophage polarisation (IL-6, MCP-1, etc.) was increased in the pre-ADSC group in the in vitro model. Pre-ADSC treatment significantly maintained blood glucose homeostasis, reduced insulin resistance, promoted islet regeneration, and ameliorated the complications related to diabetes in rats (chronic kidney disease, non-alcoholic steatohepatitis, lung fibrosis, and cataract) compared to the ADSC group (P < 0.05). Additionally, the number of anti-inflammatory M2 macrophage phenotypes was enhanced in tissues following pre-ADSC injections. Moreover, the expression of pro-inflammatory genes (iNOS, TNF-α, IL-1β) was reduced whereas that of anti-inflammatory genes (Arg1, CD206, and Il-10) was increased after cultivation with pre-ADSCs. Conclusion Diabetic microenvironment-preconditioned ADSCs effectively strengthen the capacity against inflammation and modulate the progress of long-term T2D complications.

Spatiotemporal Immunomodulation and Biphasic Osteo‐Vascular Aligned Electrospun Membrane for Diabetic Periosteum Regeneration

“…[ 37 ] To study the ability of PCLA to reprogram macrophages in the diabetic inflammatory microenvironment, the environment was initially simulated using a high‐glucose medium and lipopolysaccharides (LPS), and subsequently, the phenotypic changes of the medium macrophages seeded on the PCLA surface were examined ( Figure 4 a ). [ 38 ] In the PLA, PC, and PCL groups, the macrophages mainly adopted a pancake‐like morphology, whereas, in the PCLA group, they were elongated (Figure 4b ). Additionally, the fluorescence intensities of the M2 polarization‐related proteins markedly increased in the elongated cells on the PCLA surface, illustrating that the macrophages were polarized from the pro‐inflammatory M1 status to the anti‐inflammatory M2 status.…”

Efficacy of adipose‐derived mesenchymal stem cell therapy in the treatment of chronic micro‐ and macrovascular complications of diabetes

“…The cells lowered blood creatinine and blood urea nitrogen, and alleviated histopathological changes in interstitial tubules or glomeruli in the late-stage diabetic complications model. 85 Furthermore, hypoxia preconditioning increased the ability of ADMSCs to improve renal histological lesions such as mesangial expansion, mesangiolysis, microaneurysms and acute tubular necrosis in a rat model of DKD. 86 Interestingly, in cell-free therapy, ADMSC-derived exosomes inhibited mesangial hyperplasia and renal fibrosis, as shown by a reduction in key extracellular matrix expansion biomarkers (IL-6, collagen I or fibronectin) in a rodent model of DKD.…”

Cell therapy in end-stage liver disease: replace and remodel

“…Pro-inflammatory cytokines, such as IL-1β and IL-6, were also inhibited by MSCs [ 104 ]. Moreover, MSCs inhibit antibody production and secretion and the proliferation of activated B lymphocytes in an IDO-dependent manner [ 105 , 106 ]. In summary, the anti-inflammatory and immunomodulatory effects of MSCs can be exploited to promote liver regeneration.…”