Therapeutic effects of CD133 + Exosomes on liver function after stroke in type 2 diabetic mice

Abstract

Background and purposeNon-alcoholic fatty liver disease (NAFLD) is known to adversely affect stroke recovery. However, few studies investigate how stroke elicits liver dysfunction, particularly, how stroke in type 2 diabetes mellitus (T2DM) exacerbates progression of NAFLD. In this study, we test whether exosomes harvested from human umbilical cord blood (HUCBC) derived CD133 + cells (CD133 + Exo) improves neuro-cognitive outcome as well as reduces liver dysfunction in T2DM female mice.MethodsFemale, adult non-DM and T2DM mice subjected to stroke presence or absence were considered. T2DM-stroke mice were randomly assigned to receive PBS or Exosome treatment group. CD133 + Exo (20 μg/200 μl PBS, i.v.) was administered once at 3 days after stroke. Evaluation of neurological (mNSS, adhesive removal test) and cognitive function [novel object recognition (NOR) test, odor test] was performed. Mice were sacrificed at 28 days after stroke and brain, liver, and serum were harvested.ResultsStroke induces severe and significant short-term and long-term neurological and cognitive deficits which were worse in T2DM mice compared to non-DM mice. CD133 + Exo treatment of T2DM-stroke mice significantly improved neurological function and cognitive outcome indicated by improved discrimination index in the NOR and odor tests compared to control T2DM-stroke mice. CD133 + Exo treatment of T2DM stroke significantly increased vascular and white matter/axon remodeling in the ischemic brain compared to T2DM-stroke mice. However, there were no differences in the lesion volume between non-DM stroke, T2DM-stroke and CD133 + Exo treated T2DM-stroke mice. In T2DM mice, stroke induced earlier and higher TLR4, NLRP3, and cytokine expression (SAA, IL1β, IL6, TNFα) in the liver compared to heart and kidney, as measured by Western blot. T2DM-stroke mice exhibited worse NAFLD progression with increased liver steatosis, hepatocellular ballooning, fibrosis, serum ALT activity, and higher NAFLD Activity Score compared to T2DM mice and non-DM-stroke mice, while CD133 + Exo treatment significantly attenuated the progression of NAFLD in T2DM stroke mice.ConclusionTreatment of female T2DM-stroke mice with CD133 + Exo significantly reduces the progression of NAFLD/NASH and improves neurological and cognitive function compared to control T2DM-stroke mice.

Correlation between insulin resistance and the rate of neutrophils-lymphocytes, monocytes-lymphocytes, platelets-lymphocytes in type 2 diabetic patients

“…Importantly, the findings indicated a positive relevant between SAA levels and HOMA-IR, CRP, IL-6. SAA levels were also increased in the mouse model of diabetic stroke, which were the key factor for the progress of T2DM [ 37 ]. Our research clearly demonstrated that patients diagnosed T2DM who had IR displayed elevatory CRP and SAA levels.…”

Clinical applications of stem cell-derived exosomes

“…Using a type 2 diabetes mellitus mouse model, Venkat et al demonstrated that HSC-derived exosomes could simultaneously reduce liver dysfunction and improve neurological and cognitive function. 249 Lastly, acute pancreatitis is an unpredictable and potentially lethal disease, the prognosis of which mainly depends on whether it develops into multiple organ dysfunction syndrome. 250 Chen et al revealed that exosomes from iPSC-derived MSCs could improve myocardial injury caused by severe acute pancreatitis through the Akt/Nrf2/HO-1 pathway.…”

Enriched environment promotes neuroplasticity by regulating the ALK5/Smad2/3/Gadd45β signaling pathway in rats with cerebral ischemia/reperfusion injury

“…To investigate the role of EE in promoting neuroplasticity, we assessed the expression of DCX (a marker of neuroblasts and immature neurons) and Nestin (a neural stem cell marker) [14] and determined the infarct volume and neurobehavioral scores of rats with cerebral I/R injury [15]. We also focused on the development of axons and dendrites.…”