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

Kuan-Yin Tseng

Research output: ThesisDoctoral ThesisCollection of Articles

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 weakness in a limb to a complete loss of mobility. Currently, treatment of stroke requires a stringent rehabilitation 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.
Original languageEnglish
Awarding Institution
  • University of Helsinki
Supervisors/Advisors
  • Airavaara, Mikko, Supervisor
  • Saarma, Mart, Supervisor
  • Tuominen, Raimo K., Supervisor
Award date15 Dec 2017
Place of PublicationHelsinki
Publisher
Print ISBNs978-951-51-3902-3
Electronic ISBNs978-951-51-3903-0
Publication statusPublished - 15 Dec 2017
MoE publication typeG5 Doctoral dissertation (article)

Fields of Science

  • 3112 Neurosciences
  • 3124 Neurology and psychiatry

Cite this

@phdthesis{7dfe548ac7a24c7e9e2cba7e2db6960d,
title = "Rejuvenating the brain’s endogenous regenerative potential: focus on the role of MANF in brain development and ischemic brain injury",
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 weakness in a limb to a complete loss of mobility. Currently, treatment of stroke requires a stringent rehabilitation 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.",
keywords = "3112 Neurosciences, 3124 Neurology and psychiatry",
author = "Kuan-Yin Tseng",
year = "2017",
month = "12",
day = "15",
language = "English",
isbn = "978-951-51-3902-3",
publisher = "University of Helsinki",
address = "Finland",
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Rejuvenating the brain’s endogenous regenerative potential : focus on the role of MANF in brain development and ischemic brain injury. / Tseng, Kuan-Yin.

Helsinki : University of Helsinki, 2017. 108 p.

Research output: ThesisDoctoral ThesisCollection of Articles

TY - THES

T1 - Rejuvenating the brain’s endogenous regenerative potential

T2 - focus on the role of MANF in brain development and ischemic brain injury

AU - Tseng, Kuan-Yin

PY - 2017/12/15

Y1 - 2017/12/15

N2 - 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 weakness in a limb to a complete loss of mobility. Currently, treatment of stroke requires a stringent rehabilitation 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.

AB - 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 weakness in a limb to a complete loss of mobility. Currently, treatment of stroke requires a stringent rehabilitation 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.

KW - 3112 Neurosciences

KW - 3124 Neurology and psychiatry

M3 - Doctoral Thesis

SN - 978-951-51-3902-3

PB - University of Helsinki

CY - Helsinki

ER -