Rejuvenating the brain’s endogenous regenerative potential: focus on the role of MANF in brain development and ischemic brain injury

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Title: Rejuvenating the brain’s endogenous regenerative potential: focus on the role of MANF in brain development and ischemic brain injury
Author: Tseng, Kuan-Yin
Contributor: University of Helsinki, Faculty of Pharmacy, Division of Pharmacology and Pharmacotherapy
Institute of Biotechnology
Thesis level: Doctoral dissertation (article-based)
Abstract: Stroke is one of the leading causes of death and a major cause of disabilities in adults. More than half of stroke victims suffer some type of disability, ranging from different levels of minor weak- ness in a limb to a complete loss of mobility. Currently, treatment of stroke requires a stringent re- habilitation programs. Nevertheless, two thirds of all patients will still have some type of difficulty with regular daily activities. Recent experimental findings raise the possibility that functional improvement after stroke may be achieved through neuronal replacement by endogenous neural stem cells (NSCs) residing in the adult brain. Therefore, additional understanding of the properties of NSCs will help to identify their optimal potential in cell-based therapy. Neurotrophic factors are a family of proteins that are important in neuronal development and function, and have been studied as possible drugs for ischemic brain injury. In addition to Brain-Derived Neurotrophic Factor (BDNF) and Glial cell line-Derived Neurotrophic Factor (GDNF), Mescenphalic Astrocyte-Derived Neurotrophic Factor (MANF) and Cerebral Dopamine Neurotrophic Factor (CDNF), that form a distinct family of evolutionary conserved proteins with neuroprotective effects, have potential in the treatment of stroke. While MANF has been shown to protect cortical neurons from death in a rodent model of ischemic brain injury, the effects of post-stroke MANF ad- ministration on cellular processes during the recovery phase are poorly understood. To shed light on the possible regenerative potential of MANF for the injured brain, we need to first investigate the roles of endogenous MANF in neural stem cells (NSC) in a normal or pathological condition. We developed and optimized a work platform for studying the regulation and effect of MANF on biological properties of NSCs and cortical development. Our findings reveal an important role of MANF in neurite outgrowth and neuronal migration in the developing cortex. In addition, we demonstrated that endogenous MANF has the potential to protect NSCs against oxygen and glucose-deprivation conditions. Next, using neurosphere and subventricular zone (SVZ) explant cultures, we further studied the effect of MANF administration on cell differentiation and migration. We presented the data that exogenously added MANF can induce neural/glial differentiation and promote cell migration out of SVZ explants. Also, utilizing the advantage of NSCs as a target for MANF, we discovered that exogenous MANF can induce the phosphorylation of STAT3 in NSCs. Finally, we used the rat model of ischemic stroke to compare the effects of MANF and GDNF in neurogenesis after stroke. While injection of GDNF into lateral ventricle has a strong mitogenic effect to increase neurogenesis in SVZ, it does not induce migration of neuroblasts towards the ischemic area. In contrast, MANF facilitates the migration of neuroblasts towards the lesioned cortex. Regarding long-term infusions in the peri-infarct zone, both GDNF and MANF recruited the neuroblasts in the infarct area. However, only MANF accelerated functional recovery after stroke. In summary, this work has extended the knowledge of MANF’s capacity for neuronal differentiation as well as migration, and the regenerative capacity for its therapeutic use in further studies.Havaitsemaan MANF: n mahdollista regeneratiivista potentiaalia loukkaantuneelle aivolle meidän on ensin tutkittava endogeenisen MANF: n roolit hermoston kantasoluissa (NSC) normaalissa tai patologisessa tilassa. Kehitimme ja optimoimme työympäristön MANF: n säätelyn ja vaikutuksen tutkimiseksi NSC: n ja kortikaalisen kehityksen biologisista ominaisuuksista. Tuloksemme paljastavat MANF: n tärkeän roolin neuriittikasvussa ja hermosolujen muuttumisessa kehitettävälle aivokuorelle. Lisäksi osoitimme, että endogeenisellä MANFilla on mahdollisuus suojata NSC: itä happea ja glukoosin heikkenemisolosuhteita vastaan. Seuraavaksi, käyttämällä neurosfääri- ja subventrikulaarisia vyöhykkeitä (SVZ) eksplantaatteja, tutkittiin edelleen MANF: n antamisen vaikutusta solujen erilaistumiseen ja migraatioon. Esitimme tiedot, jotka eksogeenisesti lisäsivät MANF: ia, voivat indusoida neuraalisen / gliaalisen erilaistumisen ja edistää solujen migraatiota SVZ-eksplantaateista. Lisäksi, käyttämällä NSC: ien etua MANF: n kohteena, havaitsimme, että eksogeeninen MANF voi indusoida STAT3: n fosforylaatiota NSC: issä. Lopuksi käytimme iskeemisen aivohalvausmallin vertaamaan MANF: n ja GDNF: n vaikutuksia neurogeneesiin aivohalvauksen jälkeen.
URI: URN:ISBN:978-951-51-3902-3
Date: 2017-12-15
Rights: This publication is copyrighted. You may download, display and print it for Your own personal use. Commercial use is prohibited.

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