Cell-Based and Exosome Therapy in Diabetic Stroke

Abstract

SummaryStroke is a global health concern and it is imperative that therapeutic strategies with wide treatment time frames be developed to improve neurological outcome in patients. Patients with diabetes mellitus who suffer a stroke have worse neurological outcomes and long‐term functional recovery than nondiabetic stroke patients. Diabetes induced vascular damage and enhanced inflammatory milieu likely contributes to worse post stroke outcomes. Diabetic stroke patients have an aggravated pathological cascade, and treatments that benefit nondiabetic stroke patients do not necessarily translate to diabetic stroke patients. Therefore, there is a critical need to develop therapeutics for stroke specifically in the diabetic population. Stem cell based therapy for stroke is an emerging treatment option with wide therapeutic time window. Cell‐based therapies for stroke promote endogenous central nervous system repair and neurorestorative mechanisms such as angiogenesis, neurogenesis, vascular remodeling, white matter remodeling, and also modulate inflammatory and immune responses at the local and systemic level. Emerging evidence suggests that exosomes and their cargo microRNA mediate cell therapy derived neurorestorative effects. Exosomes are small vesicles containing protein and RNA characteristic of its parent cell. Exosomes are transported by biological fluids and facilitate communication between neighboring and remote cells. MicroRNAs, a class of naturally occurring, small noncoding RNA sequences, contained within exosomes can regulate recipient cell's signaling pathways and alter protein expression either acting alone or in concert with other microRNAs. In this perspective article, we summarize current knowledge and highlight the promising future of cell based and exosome therapy for stroke and specifically for diabetic stroke. stem cells translational medicine 2018;7:451–455

Inhibition of HDAC3 Ameliorates Cerebral Ischemia Reperfusion Injury in Diabetic Mice In Vivo and In Vitro

“…Unfortunately, the classical treatment of stroke by t-PA thrombolysis in diabetics induces an increased incidence of intracerebral hemorrhage and worse neurological outcomes compared with nondiabetic population [11]. Furthermore, some new and potential therapies that benefit nondiabetic stroke patients have failed to translate successfully into diabetic stroke counterparts [12]. Therefore, it is of great clinical significance to explore the pathogenesis and effective therapeutic strategies for diabetes complicated with stroke.…”

Ability of Post-treatment Glycyrrhizic Acid to Mitigate Cerebral Ischemia/Reperfusion Injury in Diabetic Mice

“…Uncontrolled inflammation can exacerbate brain damage after cerebral I/R [ 30 ]. Diabetes has been reported to cause continuous microglial polarization in the brain, which may exacerbate inflammation [ 31 ]. Accumulated inflammatory responses may promote cytokine release and neutrophil infiltration, leading to tissue damage and neurological deficits [ 32 ].…”

Concise Review: Stem Cell Therapy for Stroke Patients: Are We There Yet?

“…Toward stimulating these non‐neuronal repair processes, the stem cells' by‐stander effects have been proposed, including the grafted cells' ability to secrete substances that promote neurogenesis, angiogenesis, vasculogenesis, anti‐inflammation, among other therapeutic substances. Over the last 5 years, additional novel stem cell component‐based mechanisms have been demonstrated to accompany stem cell therapy, such as the transfer of stem cell‐derived mitochondria, exosomes, microvesicles, and micro‐RNAs into the ischemic area . Additionally, although stroke is traditionally considered a brain disorder, the role of peripheral organs, such as the spleen and the gut, has been implicated in the disease pathology, and that sequestration of their aberrant inflammatory and microbiome response has been deemed therapeutic, which can be achieved with stem cell transplantation .…”

“…With the notion that stem cells may confer therapeutic effects via secreted substances, there is also a translational push favoring decellularized over cellularized compositions, and such pharmacologic‐like or cell‐free treatments may benefit from the translational Stroke Treatment Academic Industry Roundtable (STAIR) criteria toward achieving the neuroprotective drug's safety profile . Specific safety deliberations are necessary when using freshly harvested, cultured, or cryopreserved cells, naked, encapsulated, or extracellular matrix‐loaded cells, and novel delivery devices such as sustained, controlled, and highly regulated nanoparticles, exosomes, extracellular vesicles, microRNAs, mitochondria, and other cellular components . The once cell‐directed transplantation approach has been replaced with much sophisticated cell components that have expanded toward emerging therapies using innovative cell‐derivative and even cell‐free compositions that will require a unique set of safety outcome evaluations.…”