Neural stem cells(NSCs)are the source of all neurons and glial cells(astrocytes and oligodendrocytes)in the central nervous system.The adult mammalian brain retains NSCs in the subgranular zone of the dentate gyrus in...Neural stem cells(NSCs)are the source of all neurons and glial cells(astrocytes and oligodendrocytes)in the central nervous system.The adult mammalian brain retains NSCs in the subgranular zone of the dentate gyrus in the hippocampus and ventricular subventricular zone lining the lateral ventricle(Olpe and Jessberger,2022).Adult NSCs in rodents are preserved throughout life and continuously produce new neurons that integrate into the pre-existing neuronal network.展开更多
Extracellular vesicles（EVs）provide a novel mechanism of intercellular communication via the transfer of proteins,lipids,and miR NAs between cells.It is now widely accepted that cargo content of EVs depends on cell t...Extracellular vesicles（EVs）provide a novel mechanism of intercellular communication via the transfer of proteins,lipids,and miR NAs between cells.It is now widely accepted that cargo content of EVs depends on cell type and its physiological state.Accordingly,EVs derived from healthy cells may have a comparable therapeutic potential as cells themselves.展开更多
Alzheimer’s disease(AD)is a major age-related form of dementia with a number of cases exponentially growing,causing enormous social and economic impact on individuals and society.Neuropathological hallmarks of AD,evi...Alzheimer’s disease(AD)is a major age-related form of dementia with a number of cases exponentially growing,causing enormous social and economic impact on individuals and society.Neuropathological hallmarks of AD,evident in postmortem AD brains,include a massive loss of the grey matter in the neocortex,extracellular deposition of amyloid-β(Aβ)in the form of senile plaques and cerebrovascular amyloid angiopathy,and intra-neuronal accumulation of neurofibrillary tangles,formed by hyper-phosphorylated tau protein.展开更多
“Last scene of all that ends this strange,eventful history,is second childishness and mere oblivion.I am sans teeth,sans eyes,sans taste,sans everything.”William Shakespeare‘As You Like It'Act 2,Sc.7,l.139Aging...“Last scene of all that ends this strange,eventful history,is second childishness and mere oblivion.I am sans teeth,sans eyes,sans taste,sans everything.”William Shakespeare‘As You Like It'Act 2,Sc.7,l.139Aging of the human brain is characterized by a progressive decline of its functional capacity;this decline however varies widely,and cognitive longevity differs substantially between individuals.展开更多
BACKGROUND ATP sensitive K+(K_(ATP))channels are ubiquitously distributed in various of cells and tissues,including the liver.They play a role in the pathogenesis of myocardial and liver ischemia.AIM To evaluate the r...BACKGROUND ATP sensitive K+(K_(ATP))channels are ubiquitously distributed in various of cells and tissues,including the liver.They play a role in the pathogenesis of myocardial and liver ischemia.AIM To evaluate the radiation-induced changes in the expression of K_(ATP)channel subunits in the mouse liver to understand the potential role of K_(ATP)channels in radiation injury.METHODS Adult C57BL/6 mice were randomly exposed toγ-rays at 0 Gy(control,n=2),0.2 Gy(n=6),1 Gy(n=6),or 5 Gy(n=6).The livers were removed 3 and 24 h after radiation exposure.Hematoxylin and eosin staining was used for morphological observation;immunohistochemical staining was applied to determine the expression of K_(ATP)channel subunits in the liver tissue.RESULTS Compared with the control group,the livers exposed to 0.2 Gyγ-ray showed an initial increase in the expression of Kir6.1 at 3 h,followed by recovery at 24 h after exposure.Exposure to a high dose of 5.0 Gy resulted in decreased expression of Kir6.1 and increased expression of SUR2B at 24 h.However,the expression of Kir6.2,SUR1,or SUR2A had no remarkable changes at 3 and 24 h after exposure to any of these doses.CONCLUSION The expression levels of Kir6.1 and SUR2B in mouse liver changed differently in response to different radiation doses,suggesting a potential role for them in radiation-induced liver injury.展开更多
The cortical grey matter of mammals has a specific cyto-architecture defined by the process of "tiling" in which protoplasmic astrocytes parcellate the nervous tissue into spatially segregated territorial do...The cortical grey matter of mammals has a specific cyto-architecture defined by the process of "tiling" in which protoplasmic astrocytes parcellate the nervous tissue into spatially segregated territorial domains.展开更多
Newts have impressive regenerative capabilities,but it remains unclear about the role of epigenetic regulation in regeneration process.We herein investigated histone modifications in newt tail tissue cells following a...Newts have impressive regenerative capabilities,but it remains unclear about the role of epigenetic regulation in regeneration process.We herein investigated histone modifications in newt tail tissue cells following amputation.lberian ribbed newts(6-8 months old)were suffered to about 1.5 cm length of amputation of their tails for initiating regeneration process,and the residual stump of tail tissues were collected for immunohistochemical analysis 3 days later.Compared to the tissue cells of intact tails,c Kit positive stem cells and PCNA positive proliferating cells were significantly higher in tails suffered to amputation.Amputation also significantly induced the acetylation of H3K9,H3K14 and H3K27 in cells of the tails with amputation,but did not significantly change the methylation of H3K27.These results suggest that epigenetic regulation likely involves in newt tail regeneration following amputation.展开更多
The blood-brain barrier(BBB)(discovered and defined by Max Lewandowsky and Lina Stern,and not,as it is universally,and yet erroneously believed,by Paul Ehrlich(Verkhratsky and Pivoriunas,2023))that separates the nervo...The blood-brain barrier(BBB)(discovered and defined by Max Lewandowsky and Lina Stern,and not,as it is universally,and yet erroneously believed,by Paul Ehrlich(Verkhratsky and Pivoriunas,2023))that separates the nervous system from the circulation is evolutionarily conserved from arthropods to man.The primeval BBB of the invertebrates and some early vertebrates was made solely by glial cells and secured(in invertebrates)by septate junctions.展开更多
Stroke causes neuronal loss,which ultimately results in persistent neurological dysfunction.Globally,stroke was the third-leading cause of death and disability combined in all ages in 2019,after neonatal disorders and...Stroke causes neuronal loss,which ultimately results in persistent neurological dysfunction.Globally,stroke was the third-leading cause of death and disability combined in all ages in 2019,after neonatal disorders and ischemic heart disease.In that year,there were 12.2 million incident strokes,101 million prevalent strokes,and 143 million disability-adjusted life-years due to stroke.展开更多
Exosome-based treatments are gaining traction as a viable approach to addressing the various issues faced by an ischemic stroke.These extracellular vesicles,mainly produced by mesenchymal stem cells,exhibit many prope...Exosome-based treatments are gaining traction as a viable approach to addressing the various issues faced by an ischemic stroke.These extracellular vesicles,mainly produced by mesenchymal stem cells,exhibit many properties with substantial therapeutic potential.Exosomes are particularly appealing for stroke therapy because of their low immunogenicity,effective cargo transport,and ability to cross the blood–brain barrier.Their diverse effects include neuroprotection,angiogenesis stimulation,inflammatory response modulation,and cell death pathway attenuation,synergistically promoting neuronal survival,tissue regeneration,and functional recovery.Exosomes also show potential as diagnostic indicators for early stroke identification and customized treatment options.Despite these promising qualities,current exosome-based therapeutics have some limitations.The heterogeneity of exosome release among cell types,difficulty in standardization and isolation techniques,and complications linked to dosage and targeted administration necessitates extensive investigation.It is critical to thoroughly understand exosomal processes and their complicated interactions within the cellular milieu.To improve the practicality and efficacy of exosome-based medicines,research efforts must focus on improving production processes,developing robust evaluation criteria,and developing large-scale isolation techniques.Altogether,exosomes’multifunctional properties offer a new route for transforming stroke treatment and significantly improving patient outcomes.展开更多
A sharply transected spinal cord has been shown to be fused under the accelerating influence of membrane fusogens such as polyethylene glycol （PEG） （GEMINI protocol）. Previous work provided evidence that this is i...A sharply transected spinal cord has been shown to be fused under the accelerating influence of membrane fusogens such as polyethylene glycol （PEG） （GEMINI protocol）. Previous work provided evidence that this is in fact possible. Other fusogens might improve current results. In this study, we aimed to assess the effects of PEGylated graphene nanoribons （PEG-GNR, and called ＂TexasPEG＂ when prepared as lwt% dispersion in PEG600） versus placebo （saline） on locomotor function recovery and cellular level in a rat model of spinal cord transection at lumbar segment 1 （L1） level. In vivo and in vitro experiments （n -- 10 per experiment） were designed. In the in vivo experiment, all rats were submitted to full spinal cord transection at L1 level. Five weeks later, behavioral assessment was performed using the Basso Beattie Bresnahan （BBB） locomotor rating scale. Immunohistochemical staining with neuron marker neurofilament 200 （NF200） antibody and astrocyt- ic scar marker glial fibrillary acidic protein （GFAP） was also performed in the injured spinal cord. In the in vitro experiment, the effects of TexasPEG application for 72 hours on the neurite outgrowth of SH-SYSY cells were observed under the inverted microscope. Results of both in vivo and in vitro experiments suggest that TexasPEG reduces the formation of glial scars, promotes the regeneration of neurites, and thereby contributes to the recovery of locomotor function of a rat model of spinal cord transfection.展开更多
It is generally accepted that a severed spinal cord is associated with permanent paralysis.Recently,a spinal cord fusion protocol（GEMINI）has been proposed,whereby an acutely controlled,sharp,operative transection of...It is generally accepted that a severed spinal cord is associated with permanent paralysis.Recently,a spinal cord fusion protocol（GEMINI）has been proposed,whereby an acutely controlled,sharp,operative transection of the spinal cord is carried out.展开更多
BACKGROUND ATP-sensitive K^+(KATP)channels were originally found in cardiac myocytes by Noma in 1983.KATP channels were formed by potassium ion-passing poreforming subunits(Kir6.1,Kir6.2)and regulatory subunits SUR1,S...BACKGROUND ATP-sensitive K^+(KATP)channels were originally found in cardiac myocytes by Noma in 1983.KATP channels were formed by potassium ion-passing poreforming subunits(Kir6.1,Kir6.2)and regulatory subunits SUR1,SU2A and SUR2B.A number of cells and tissues have been revealed to contain these channels including hepatocytes,but detailed localization of these subunits in different types of liver cells was still uncertain.AIM To investigate the expression of KATP channel subunits in rat liver and their localization in different cells of the liver.METHODS Rabbit anti-rat SUR1 peptide antibody was raised and purified by antigen immunoaffinity column chromatography.Four of Sprague-Dawley rats were used for liver protein extraction for immunoblot analysis,seven of them were used for immunohistochemistry both for the ABC method and immunofluorescence staining.Four of Wistar rats were used for the isolation of hepatic stellate cells(HSCs)and Kupffer cells for both primary culture and immunocytochemistry.RESULTS Immunoblot analysis showed that the five kinds of KATP channel subunits,i.e.Kir6.1,Kir6.2,SUR1,SUR2A,and SUR2B,were detected in liver.Immunohistochemical staining showed that Kir6.1 and Kir6.2 were weakly to moderately expressed in parenchymal cells and sinusoidal lining cells,while SUR1,SUR2A,and SUR2B were mainly localized to sinusoidal lining cells,such as HSCs,Kupffer cells,and sinusoidal endothelial cells.Immunoreactivity for SUR2A and SUR2B was expressed in the hepatocyte membrane.Double immunofluorescence staining further showed that the pore-forming subunits Kir6.1 and/or Kir6.2 colocalized with GFAP in rat liver sections and primary cultured HSCs.These KATP channel subunits also colocalized with CD68 in liver sections and primary cultured Kupffer cells.The SUR subunits colocalized with GFAP in liver sections and colocalized with CD68 both in liver sections and primary cultured Kupffer cells.In addition,five KATP channel subunits colocalized with SE-1 in sinusoidal endothelial cells.CONCLUSION Observations from the present study indicated that KATP channel subunits expressed in rat liver and the diversity of KATP channel subunit composition might form different types of KATP channels.This is applicable to hepatocytes,HSCs,various types of Kupffer cells and sinusoidal endothelial cells.展开更多
The functional realization is the most important problem in vascular tissue engineering. The small-caliber blood vessel substitutes are prone to thrombi, which results in functional loss of blood vessels. However, thi...The functional realization is the most important problem in vascular tissue engineering. The small-caliber blood vessel substitutes are prone to thrombi, which results in functional loss of blood vessels. However, this is probably due to the imper- fection of endothelial layer in the substitutes. In this study, MSCs were seeded on a series of porous PLGA films with various porosity and pore size made by sodium chloride (NaCl) particulate leaching, and cell proliferation on each film was inspected. The film made of the 75% (w/w) particulate proportion and 30―50 μm pore size maximized the proliferation rate and was chosen as the scaffolds for the differentia- tion of MSCs into endothelial cells. The induced cells expressed endothelial cells specific Flk-1, Ⅷ factor and CD34, possessed endothelial cells specific Weible-palade (W-P) body, and had the abilities of ingesting low density lipoprotein and secreting prostacyclin (PGI2). The results show that MSCs not only have the ideal biological compatibility with the porous PLGA films, but also have the potency of dif- ferentiating into functional endothelial cells, whichshould facilitate the endothelialization in vascular tissue engineering.展开更多
Human induced pluripotent stem （hiPS） cells are considered a potential source for the generation of insulin-producing pancreatic β-ceUs because of their differentiation capacity. In this study, we have developed a ...Human induced pluripotent stem （hiPS） cells are considered a potential source for the generation of insulin-producing pancreatic β-ceUs because of their differentiation capacity. In this study, we have developed a five-step xeno-free culture system to efficiently dif- ferentiate hiPS cells into insulin-producing cells in vitro. We found that a high NOGGIN concentration is crucial for specifically inducing the differentiation first into pancreatic and duodenal homeobox-1 （PDX1）-positive pancreatic progenitors and then into neurogenin 3 （NGN3）-expressing pancreatic endocrine progenitors, while suppressing the differentiation into hepatic or intestinal cells. We also found that a combination of 3-isobutyl-l-methylxanthine （IBMX）, exendin-4, and nicotinamide was important for the differentiation into insulin single-positive cells that expressed various pancreatic β-cell markers. Most notably, the differentiated cells contained en- dogenous C-peptide pools that were released in response to various insulin secretagogues and high levels of glucose. Therefore, our results demonstrate the feasibility of generating hiPS-derived pancreatic β-ceUs under xeno-free conditions and highlight their poten- tial to treat patients with type I diabetes.展开更多
Embryonic stem cells （ESCs） maintain their cellular identity through the systematic regulation of master transcription factors and chromatin remodeling complexes. Recent work has shown that the unusually large-scale...Embryonic stem cells （ESCs） maintain their cellular identity through the systematic regulation of master transcription factors and chromatin remodeling complexes. Recent work has shown that the unusually large-scale enhancers-namely super-enhancers （SEs）, on which BRD4, a member of the bromodomain and extraterminal domain （BET） family is highly enriched-could regulate pluripotency-related transcrip- tion factors. Moreover, inhibition of BRD4 binding on SEs has been shown to induce the differentiation of ESCs. However, the underlying mechanism of BRD4 inhibition-mediated stern cell differentiation remains elusive. Here we show that both mouse and human ESCs lose their capacity for self-renewal upon treat- ment with JQ1, a selective inhibitor of BET family including BRD4, with rapid suppression of pluripotency-associated genes. Notably, a high concentration of JQI could selectively eliminate ESCs via apoptosis, without affecting the functionality of differentiated somatic cells from ESCs, suggesting that inhibition of BET may have a beneficial effect on the development of pluripotent stem cell-based cell therapy.展开更多
BACKGROUND： Recently, growing attention has been directed toward stem cell metabolism, with the key observation that metabolism not only fuels the proper functioning of stem cells but also regulates the fate of these...BACKGROUND： Recently, growing attention has been directed toward stem cell metabolism, with the key observation that metabolism not only fuels the proper functioning of stem cells but also regulates the fate of these cells. There seems to be a clear link between the self-renewal ofpluripotent stem cells （PSCs）, in which cells proliferate indefinitely without differentiation, and the activity of specific metabolic pathways. The unique metabolism in PSCs plays an important role in maintaining pluripotency by regulating signaling pathways and resetting the epigenome. OBJECTIVE： To review the most recent publications concerning the metabolism of pluripotent stem cells and the role of metabolism in PSC self-renewal and differentiation. METHODS： A systematic literature search related to the metabolism of PSCs was conducted in databases including Medline, Embase, and Web of Science. The search was performed without language restrictions on all papers published before May 2016. The following keywords were used： ＂metabolism＂ combined with either ＂embryonic stem cell＂ or ＂epiblast stem cell.＂ RESULTS： Hundreds of papers focusing specifically on the metabolism of pluripotent stem cells were uncovered and summarized. CONCLUSION： Identifying the specific metabolic pathways involved in pluripotency maintenance is crucial for progress in the field of developmental biology and regenerative medicine. Additionally, better understanding of the metabolism in PSCs will facilitate the derivation and maintenance of authentic PSCs from species other than mouse, rat, and human.展开更多
Glioblastomas(GBMs)are highly lethal primary brain tumors.Despite current therapeutic advances in other solid cancers,the treatment of these malignant gliomas remains essentially palliative.GBMs are extremely resistan...Glioblastomas(GBMs)are highly lethal primary brain tumors.Despite current therapeutic advances in other solid cancers,the treatment of these malignant gliomas remains essentially palliative.GBMs are extremely resistant to conventional radiation and chemotherapies.We and others have demonstrated that a highly tumorigenic subpopulation of cancer cells called GBM stem cells(GSCs)promotes therapeutic resistance.We also found that GSCs stimulate tumor angiogenesis by expressing elevated levels of VEGF and contribute to tumor growth,which has been translated into a useful therapeutic strategy in the treatment of recurrent or progressive GBMs.Furthermore,stem cell-like cancer cells(cancer stem cells)have been shown to promote metastasis.Although GBMs rarely metastasize beyond the central nervous system,these highly infiltrative cancers often invade into normal brain tissues preventing surgical resection,and GSCs display an aggressive invasive phenotype.These studies suggest that targeting GSCs may effectively reduce tumor recurrence and significantly improve GBM treatment.Recent studies indicate that cancer stem cells share core signaling pathways with normal somatic or embryonic stem cells,but also display critical distinctions that provide important clues into useful therapeutic targets.In this review,we summarize the current understanding and advances in glioma stem cell research,and discuss potential targeting strategies for future development of anti-GSC therapies.展开更多
Uncovering the molecular pathways that drive skeletal repair has been an ongoing challenge. Initial efforts have relied on in vitro assays to identify the key signaling pathways that drive cartilage and bone different...Uncovering the molecular pathways that drive skeletal repair has been an ongoing challenge. Initial efforts have relied on in vitro assays to identify the key signaling pathways that drive cartilage and bone differentiation. While these assays can provide some clues, assessing specific pathways in animal models is critical. Furthermore, definitive proof that a pathway is required for skeletal repair is best provided using genetic tests. Stimulating the Hh(Hedgehog) pathway can promote cartilage and bone differentiation in cell culture assays. In addition, the application of HH protein or various pathway agonists in vivo has a positive influence on bone healing. Until recently, however, genetic proof that the Hh pathway is involved in bone repair has been lacking. Here, we consider both in vitro and in vivo studies that examine the role of Hh in repair and discuss some of the challenges inherent in their interpretation. We also identify needed areas of study considering a new appreciation for the role of cartilage during repair, the variety of cell types that may have differing roles in repair, and the recent availability of powerful lineage tracing techniques. We are optimistic that emerging genetic tools will make it possible to precisely define when and in which cells promoting Hh signaling can best promote skeletal repair, and thus, the clinical potential for targeting the Hh pathway can be realized.展开更多
基金supported by a Grant-in-Aid for Scientific Research(B)JP21H02808(to TM)JST SPRING JPMJSP2136(to MI)。
文摘Neural stem cells(NSCs)are the source of all neurons and glial cells(astrocytes and oligodendrocytes)in the central nervous system.The adult mammalian brain retains NSCs in the subgranular zone of the dentate gyrus in the hippocampus and ventricular subventricular zone lining the lateral ventricle(Olpe and Jessberger,2022).Adult NSCs in rodents are preserved throughout life and continuously produce new neurons that integrate into the pre-existing neuronal network.
基金supported by National Research Programme,“Healthy ageing”(Grant No.SEN-15090)from Research Council of Lithuania
文摘Extracellular vesicles（EVs）provide a novel mechanism of intercellular communication via the transfer of proteins,lipids,and miR NAs between cells.It is now widely accepted that cargo content of EVs depends on cell type and its physiological state.Accordingly,EVs derived from healthy cells may have a comparable therapeutic potential as cells themselves.
基金the following financial support grant FAR-2019 to DL from The Universita del Piemonte Orientale。
文摘Alzheimer’s disease(AD)is a major age-related form of dementia with a number of cases exponentially growing,causing enormous social and economic impact on individuals and society.Neuropathological hallmarks of AD,evident in postmortem AD brains,include a massive loss of the grey matter in the neocortex,extracellular deposition of amyloid-β(Aβ)in the form of senile plaques and cerebrovascular amyloid angiopathy,and intra-neuronal accumulation of neurofibrillary tangles,formed by hyper-phosphorylated tau protein.
文摘“Last scene of all that ends this strange,eventful history,is second childishness and mere oblivion.I am sans teeth,sans eyes,sans taste,sans everything.”William Shakespeare‘As You Like It'Act 2,Sc.7,l.139Aging of the human brain is characterized by a progressive decline of its functional capacity;this decline however varies widely,and cognitive longevity differs substantially between individuals.
基金Supported by the Program of the Network-type Joint Usage/Research Center for Radiation Disaster Medical Science of Hiroshima University,Nagasaki University.
文摘BACKGROUND ATP sensitive K+(K_(ATP))channels are ubiquitously distributed in various of cells and tissues,including the liver.They play a role in the pathogenesis of myocardial and liver ischemia.AIM To evaluate the radiation-induced changes in the expression of K_(ATP)channel subunits in the mouse liver to understand the potential role of K_(ATP)channels in radiation injury.METHODS Adult C57BL/6 mice were randomly exposed toγ-rays at 0 Gy(control,n=2),0.2 Gy(n=6),1 Gy(n=6),or 5 Gy(n=6).The livers were removed 3 and 24 h after radiation exposure.Hematoxylin and eosin staining was used for morphological observation;immunohistochemical staining was applied to determine the expression of K_(ATP)channel subunits in the liver tissue.RESULTS Compared with the control group,the livers exposed to 0.2 Gyγ-ray showed an initial increase in the expression of Kir6.1 at 3 h,followed by recovery at 24 h after exposure.Exposure to a high dose of 5.0 Gy resulted in decreased expression of Kir6.1 and increased expression of SUR2B at 24 h.However,the expression of Kir6.2,SUR1,or SUR2A had no remarkable changes at 3 and 24 h after exposure to any of these doses.CONCLUSION The expression levels of Kir6.1 and SUR2B in mouse liver changed differently in response to different radiation doses,suggesting a potential role for them in radiation-induced liver injury.
基金supported by the Global Grant measure (No.09.3.3-LMTK-712-01-0082to AP and AV)。
文摘The cortical grey matter of mammals has a specific cyto-architecture defined by the process of "tiling" in which protoplasmic astrocytes parcellate the nervous tissue into spatially segregated territorial domains.
文摘Newts have impressive regenerative capabilities,but it remains unclear about the role of epigenetic regulation in regeneration process.We herein investigated histone modifications in newt tail tissue cells following amputation.lberian ribbed newts(6-8 months old)were suffered to about 1.5 cm length of amputation of their tails for initiating regeneration process,and the residual stump of tail tissues were collected for immunohistochemical analysis 3 days later.Compared to the tissue cells of intact tails,c Kit positive stem cells and PCNA positive proliferating cells were significantly higher in tails suffered to amputation.Amputation also significantly induced the acetylation of H3K9,H3K14 and H3K27 in cells of the tails with amputation,but did not significantly change the methylation of H3K27.These results suggest that epigenetic regulation likely involves in newt tail regeneration following amputation.
基金funding from European Regional Development Fund(project No 13.1.1-LMT-K-718-05-0005)under grant agreement with the Research Council of Lithuania(LMTLT)。
文摘The blood-brain barrier(BBB)(discovered and defined by Max Lewandowsky and Lina Stern,and not,as it is universally,and yet erroneously believed,by Paul Ehrlich(Verkhratsky and Pivoriunas,2023))that separates the nervous system from the circulation is evolutionarily conserved from arthropods to man.The primeval BBB of the invertebrates and some early vertebrates was made solely by glial cells and secured(in invertebrates)by septate junctions.
基金supported by JSPS KAKENHI Grant Number JP24K18622(to TI)JSPS KAKENHI Grant Number JP23K18451(to TM)。
文摘Stroke causes neuronal loss,which ultimately results in persistent neurological dysfunction.Globally,stroke was the third-leading cause of death and disability combined in all ages in 2019,after neonatal disorders and ischemic heart disease.In that year,there were 12.2 million incident strokes,101 million prevalent strokes,and 143 million disability-adjusted life-years due to stroke.
基金National Institutes of Health,Grant/Award Number:NIH R21NS133531。
文摘Exosome-based treatments are gaining traction as a viable approach to addressing the various issues faced by an ischemic stroke.These extracellular vesicles,mainly produced by mesenchymal stem cells,exhibit many properties with substantial therapeutic potential.Exosomes are particularly appealing for stroke therapy because of their low immunogenicity,effective cargo transport,and ability to cross the blood–brain barrier.Their diverse effects include neuroprotection,angiogenesis stimulation,inflammatory response modulation,and cell death pathway attenuation,synergistically promoting neuronal survival,tissue regeneration,and functional recovery.Exosomes also show potential as diagnostic indicators for early stroke identification and customized treatment options.Despite these promising qualities,current exosome-based therapeutics have some limitations.The heterogeneity of exosome release among cell types,difficulty in standardization and isolation techniques,and complications linked to dosage and targeted administration necessitates extensive investigation.It is critical to thoroughly understand exosomal processes and their complicated interactions within the cellular milieu.To improve the practicality and efficacy of exosome-based medicines,research efforts must focus on improving production processes,developing robust evaluation criteria,and developing large-scale isolation techniques.Altogether,exosomes’multifunctional properties offer a new route for transforming stroke treatment and significantly improving patient outcomes.
基金supported by a grant from the National Research Foundation(NRF)funded by the Korean government(NRF-2015M3A9C7030091 and NRF-2015R1C1A1A02037047)
文摘A sharply transected spinal cord has been shown to be fused under the accelerating influence of membrane fusogens such as polyethylene glycol （PEG） （GEMINI protocol）. Previous work provided evidence that this is in fact possible. Other fusogens might improve current results. In this study, we aimed to assess the effects of PEGylated graphene nanoribons （PEG-GNR, and called ＂TexasPEG＂ when prepared as lwt% dispersion in PEG600） versus placebo （saline） on locomotor function recovery and cellular level in a rat model of spinal cord transection at lumbar segment 1 （L1） level. In vivo and in vitro experiments （n -- 10 per experiment） were designed. In the in vivo experiment, all rats were submitted to full spinal cord transection at L1 level. Five weeks later, behavioral assessment was performed using the Basso Beattie Bresnahan （BBB） locomotor rating scale. Immunohistochemical staining with neuron marker neurofilament 200 （NF200） antibody and astrocyt- ic scar marker glial fibrillary acidic protein （GFAP） was also performed in the injured spinal cord. In the in vitro experiment, the effects of TexasPEG application for 72 hours on the neurite outgrowth of SH-SYSY cells were observed under the inverted microscope. Results of both in vivo and in vitro experiments suggest that TexasPEG reduces the formation of glial scars, promotes the regeneration of neurites, and thereby contributes to the recovery of locomotor function of a rat model of spinal cord transfection.
基金supported by the National Research Foundation of Korea(NRF),No.2015R1C1A1A02037047
文摘It is generally accepted that a severed spinal cord is associated with permanent paralysis.Recently,a spinal cord fusion protocol（GEMINI）has been proposed,whereby an acutely controlled,sharp,operative transection of the spinal cord is carried out.
基金Supported by the Program of the network-type joint Usage/Research Center for Radiation Disaster Medical Science of Hiroshima University,Nagasaki University,and Fukushima Medical University
文摘BACKGROUND ATP-sensitive K^+(KATP)channels were originally found in cardiac myocytes by Noma in 1983.KATP channels were formed by potassium ion-passing poreforming subunits(Kir6.1,Kir6.2)and regulatory subunits SUR1,SU2A and SUR2B.A number of cells and tissues have been revealed to contain these channels including hepatocytes,but detailed localization of these subunits in different types of liver cells was still uncertain.AIM To investigate the expression of KATP channel subunits in rat liver and their localization in different cells of the liver.METHODS Rabbit anti-rat SUR1 peptide antibody was raised and purified by antigen immunoaffinity column chromatography.Four of Sprague-Dawley rats were used for liver protein extraction for immunoblot analysis,seven of them were used for immunohistochemistry both for the ABC method and immunofluorescence staining.Four of Wistar rats were used for the isolation of hepatic stellate cells(HSCs)and Kupffer cells for both primary culture and immunocytochemistry.RESULTS Immunoblot analysis showed that the five kinds of KATP channel subunits,i.e.Kir6.1,Kir6.2,SUR1,SUR2A,and SUR2B,were detected in liver.Immunohistochemical staining showed that Kir6.1 and Kir6.2 were weakly to moderately expressed in parenchymal cells and sinusoidal lining cells,while SUR1,SUR2A,and SUR2B were mainly localized to sinusoidal lining cells,such as HSCs,Kupffer cells,and sinusoidal endothelial cells.Immunoreactivity for SUR2A and SUR2B was expressed in the hepatocyte membrane.Double immunofluorescence staining further showed that the pore-forming subunits Kir6.1 and/or Kir6.2 colocalized with GFAP in rat liver sections and primary cultured HSCs.These KATP channel subunits also colocalized with CD68 in liver sections and primary cultured Kupffer cells.The SUR subunits colocalized with GFAP in liver sections and colocalized with CD68 both in liver sections and primary cultured Kupffer cells.In addition,five KATP channel subunits colocalized with SE-1 in sinusoidal endothelial cells.CONCLUSION Observations from the present study indicated that KATP channel subunits expressed in rat liver and the diversity of KATP channel subunit composition might form different types of KATP channels.This is applicable to hepatocytes,HSCs,various types of Kupffer cells and sinusoidal endothelial cells.
文摘The functional realization is the most important problem in vascular tissue engineering. The small-caliber blood vessel substitutes are prone to thrombi, which results in functional loss of blood vessels. However, this is probably due to the imper- fection of endothelial layer in the substitutes. In this study, MSCs were seeded on a series of porous PLGA films with various porosity and pore size made by sodium chloride (NaCl) particulate leaching, and cell proliferation on each film was inspected. The film made of the 75% (w/w) particulate proportion and 30―50 μm pore size maximized the proliferation rate and was chosen as the scaffolds for the differentia- tion of MSCs into endothelial cells. The induced cells expressed endothelial cells specific Flk-1, Ⅷ factor and CD34, possessed endothelial cells specific Weible-palade (W-P) body, and had the abilities of ingesting low density lipoprotein and secreting prostacyclin (PGI2). The results show that MSCs not only have the ideal biological compatibility with the porous PLGA films, but also have the potency of dif- ferentiating into functional endothelial cells, whichshould facilitate the endothelialization in vascular tissue engineering.
文摘Human induced pluripotent stem （hiPS） cells are considered a potential source for the generation of insulin-producing pancreatic β-ceUs because of their differentiation capacity. In this study, we have developed a five-step xeno-free culture system to efficiently dif- ferentiate hiPS cells into insulin-producing cells in vitro. We found that a high NOGGIN concentration is crucial for specifically inducing the differentiation first into pancreatic and duodenal homeobox-1 （PDX1）-positive pancreatic progenitors and then into neurogenin 3 （NGN3）-expressing pancreatic endocrine progenitors, while suppressing the differentiation into hepatic or intestinal cells. We also found that a combination of 3-isobutyl-l-methylxanthine （IBMX）, exendin-4, and nicotinamide was important for the differentiation into insulin single-positive cells that expressed various pancreatic β-cell markers. Most notably, the differentiated cells contained en- dogenous C-peptide pools that were released in response to various insulin secretagogues and high levels of glucose. Therefore, our results demonstrate the feasibility of generating hiPS-derived pancreatic β-ceUs under xeno-free conditions and highlight their poten- tial to treat patients with type I diabetes.
基金supported by the National Research Foundation of Korea(NRF-2016K1A3A1A61006005,NRF-2016R1A2B3011860,NRF-2016R1A5A2012284,and NRF-2017M3C7A1047640)
文摘Embryonic stem cells （ESCs） maintain their cellular identity through the systematic regulation of master transcription factors and chromatin remodeling complexes. Recent work has shown that the unusually large-scale enhancers-namely super-enhancers （SEs）, on which BRD4, a member of the bromodomain and extraterminal domain （BET） family is highly enriched-could regulate pluripotency-related transcrip- tion factors. Moreover, inhibition of BRD4 binding on SEs has been shown to induce the differentiation of ESCs. However, the underlying mechanism of BRD4 inhibition-mediated stern cell differentiation remains elusive. Here we show that both mouse and human ESCs lose their capacity for self-renewal upon treat- ment with JQ1, a selective inhibitor of BET family including BRD4, with rapid suppression of pluripotency-associated genes. Notably, a high concentration of JQI could selectively eliminate ESCs via apoptosis, without affecting the functionality of differentiated somatic cells from ESCs, suggesting that inhibition of BET may have a beneficial effect on the development of pluripotent stem cell-based cell therapy.
文摘BACKGROUND： Recently, growing attention has been directed toward stem cell metabolism, with the key observation that metabolism not only fuels the proper functioning of stem cells but also regulates the fate of these cells. There seems to be a clear link between the self-renewal ofpluripotent stem cells （PSCs）, in which cells proliferate indefinitely without differentiation, and the activity of specific metabolic pathways. The unique metabolism in PSCs plays an important role in maintaining pluripotency by regulating signaling pathways and resetting the epigenome. OBJECTIVE： To review the most recent publications concerning the metabolism of pluripotent stem cells and the role of metabolism in PSC self-renewal and differentiation. METHODS： A systematic literature search related to the metabolism of PSCs was conducted in databases including Medline, Embase, and Web of Science. The search was performed without language restrictions on all papers published before May 2016. The following keywords were used： ＂metabolism＂ combined with either ＂embryonic stem cell＂ or ＂epiblast stem cell.＂ RESULTS： Hundreds of papers focusing specifically on the metabolism of pluripotent stem cells were uncovered and summarized. CONCLUSION： Identifying the specific metabolic pathways involved in pluripotency maintenance is crucial for progress in the field of developmental biology and regenerative medicine. Additionally, better understanding of the metabolism in PSCs will facilitate the derivation and maintenance of authentic PSCs from species other than mouse, rat, and human.
文摘Glioblastomas(GBMs)are highly lethal primary brain tumors.Despite current therapeutic advances in other solid cancers,the treatment of these malignant gliomas remains essentially palliative.GBMs are extremely resistant to conventional radiation and chemotherapies.We and others have demonstrated that a highly tumorigenic subpopulation of cancer cells called GBM stem cells(GSCs)promotes therapeutic resistance.We also found that GSCs stimulate tumor angiogenesis by expressing elevated levels of VEGF and contribute to tumor growth,which has been translated into a useful therapeutic strategy in the treatment of recurrent or progressive GBMs.Furthermore,stem cell-like cancer cells(cancer stem cells)have been shown to promote metastasis.Although GBMs rarely metastasize beyond the central nervous system,these highly infiltrative cancers often invade into normal brain tissues preventing surgical resection,and GSCs display an aggressive invasive phenotype.These studies suggest that targeting GSCs may effectively reduce tumor recurrence and significantly improve GBM treatment.Recent studies indicate that cancer stem cells share core signaling pathways with normal somatic or embryonic stem cells,but also display critical distinctions that provide important clues into useful therapeutic targets.In this review,we summarize the current understanding and advances in glioma stem cell research,and discuss potential targeting strategies for future development of anti-GSC therapies.
基金supported by NICHD T32 training grants(S.T.K.,S.L.,M.S.)the Roy E.Thomas Graduate Scholarship(M.S.)by NIAMS AR069700(F.V.M).
文摘Uncovering the molecular pathways that drive skeletal repair has been an ongoing challenge. Initial efforts have relied on in vitro assays to identify the key signaling pathways that drive cartilage and bone differentiation. While these assays can provide some clues, assessing specific pathways in animal models is critical. Furthermore, definitive proof that a pathway is required for skeletal repair is best provided using genetic tests. Stimulating the Hh(Hedgehog) pathway can promote cartilage and bone differentiation in cell culture assays. In addition, the application of HH protein or various pathway agonists in vivo has a positive influence on bone healing. Until recently, however, genetic proof that the Hh pathway is involved in bone repair has been lacking. Here, we consider both in vitro and in vivo studies that examine the role of Hh in repair and discuss some of the challenges inherent in their interpretation. We also identify needed areas of study considering a new appreciation for the role of cartilage during repair, the variety of cell types that may have differing roles in repair, and the recent availability of powerful lineage tracing techniques. We are optimistic that emerging genetic tools will make it possible to precisely define when and in which cells promoting Hh signaling can best promote skeletal repair, and thus, the clinical potential for targeting the Hh pathway can be realized.
