Background In order to suggest an ideal source of adult stem cells for the treatment of nervous system diseases,MSCs from human adipose tissue and bone marrow were isolated and studied to explore the differences with ...Background In order to suggest an ideal source of adult stem cells for the treatment of nervous system diseases,MSCs from human adipose tissue and bone marrow were isolated and studied to explore the differences with regard to cell morphology,surface markers,neuronal differentiation capacity,especially the synapse structure formation and the secretion of neurotrophic factors.Methods The neuronal differentiation capacity of human mesenchymal stem cells from adipose tissue （hADSCs） and bone marrow （hBMSCs） was determined based on nissl body and synapse structure formation,and neural factor secretion function.hADSCs and hBMSCs were isolated and differentiated into neuron-like cells with rat brain-conditioned medium,a potentially rich source of neuronal differentiation promoting signals.Specific neuronal proteins and neural factors were detected by immunohistochemistry and enzyme-linked immunosorbent assay analysis,respectively.Results Flow cytometric analysis showed that both cell types had similar phenotypes.Cell growth curves showed that hADSCs proliferated more quickly than hBMSCs.Both kinds of cells were capable of osteogenic and adipogenic differentiation.The morphology of hADSCs and hBMSCs changed during neuronal differentiation and displayed neuronlike cell appearance after 14 days＇ differentiation.Both hADSCs and hBMSCs were able to differentiate into neuron-like cells based on their production of neuron specific proteins including β-tubulin-Ⅲ,neuron-specific enolase （NSE）,nissl bodies,and their ability to secrete brain derived neurotrophic factor （BDNF） and nerve growth factor （NGF）.Assessment of synaptop hysin and growth-associated protein-43 （GAP-43） suggested synapse structure formation in differentiated hADSCs and hBMSCs.Conclusions Our results demonstrate that hADSCs have neuronal differentiation potential similar to hBMSC,but with a higher proliferation capacity than hBMSC.Adipose tissue is abundant,easily available and would be a potential ideal source of adult stem cells展开更多
MicroRNAs play important roles in post-transcriptional regulation of gene expression by inhibiting protein translation and/or promoting mRNA degradation.Importantly,biogenesis of microRNAs displays specific temporal a...MicroRNAs play important roles in post-transcriptional regulation of gene expression by inhibiting protein translation and/or promoting mRNA degradation.Importantly,biogenesis of microRNAs displays specific temporal and spatial profiles in distinct cell and tissue types and hence affects a broad spectrum of biological functions in normal cell growth and tumor development.Recent discoveries have revealed sophisticated mechanisms that control microRNA production and homeostasis in response to developmental and extracellular signals.Moreover,a link between dysregulation of microRNAs and human brain disorders has become increasingly evident.In this review,we focus on recent advances in understanding the regulation of microRNA biogenesis and function in neuronal and glial development in the mammalian brain,and dysregulation of the microRNA pathway in neurodevelopmental and neurodegenerative diseases.展开更多
Recent studies have identified mutations in PHF8, an X-linked gene encoding a JmjC domain-containing protein, as a causal factor for X-linked mental retardation （XLMR） and cleft lip/cleft palate. However, the underl...Recent studies have identified mutations in PHF8, an X-linked gene encoding a JmjC domain-containing protein, as a causal factor for X-linked mental retardation （XLMR） and cleft lip/cleft palate. However, the underlying mechanism is unknown. Here we show that PHF8 is a histone demethylase and coactivator for retinoic acid receptor （RAR）. Although activities for both H3K4me3/2/1 and H3K9me2/1 demethylation were detected in cellularbased assays, reeombinant PHF8 exhibited only H3K9me2/1 demethylase activity in vitro, suggesting that PHF8 is an H3K9me2/1 demethylase whose specificity may be modulated in vivo. Importantly, a mutant PHF8 （phenylalanine at position 279 to serine） identified in the XLMR patients is defective in enzymatie activity, indicating that the loss of histone demethylase activity is causally linked with the onset of disease. In addition, we show that PHF8 binds specifically to H3K4me3/2 peptides via an N-terminal PHD finger domain. Consistent with a role for PHF8 in neuronal differentiation, knockdown of PHF8 in mouse embryonic carcinoma P19 cells impairs RA-induced neuronal differentiation, whereas overexpression of the wild-type but not the F279S mutant PHF8 drives PI9 cells toward neuronal differentiation. Furthermore, we show that PHF8 interacts with RAR~ and functions as a coactivator for RARa. Taken together, our results suggest that histone methylation modulated by PHF8 plays a critical role in neuronal differentiation.展开更多
Bone marrow-derived mesenchymal stem cells differentiate into neurons under the induction of Schwann cells. However, key microRNAs and related pathways for differentiation remain unclear. This study screened and ident...Bone marrow-derived mesenchymal stem cells differentiate into neurons under the induction of Schwann cells. However, key microRNAs and related pathways for differentiation remain unclear. This study screened and identified differentially expressed microRNAs in bone marrow- derived mesenchymal stem cells induced by Schwann cell-conditioned medium, and explored targets and related pathways involved in their differentiation into neuronal-like cells. Primary bone marrow-derived mesenchymal stem cells were isolated from femoral and tibial bones, while primary Schwann cells were isolated from bilateral saphenous nerves. Bone marrow-derived mesenchymal stem cells were cultured in unconditioned (control group) and Schwann cell-conditioned medium (bone marrow-derived mesenchymal stem cell + Schwann cell group). Neuronal differentiation of bone marrow-derived mesenchymal stem cells induced by Schwann cell-conditioned medium was observed by time-lapse imaging. Upon induction, the morphology of bone marrow-derived mesencaymal stem cells changed into a neural shape with neurites. Results of quantitative reverse transcription-polymerase chain reaction revealed that nestin mRNA expression was upregulated from 1 to 3 days and downregulated from 3 to 7 days in the bone marrow-derived mesenchymal stem cell + Schwann cell group. Compared with the control group, microtubule-associated protein 2 mRNA expression gradually increased from 1 to 7 days in the bone marrow-derived mesenchymal stem cell + Schwann cell group. After 7 days of induction, microRNA analysis iden:ified 83 significantly differentially expressed microRNAs between the two groups. Gene Ontology analysis indicated enrichment of microRNA target genes for neuronal projection development, regulation of axonogenesis, and positive regulation of cell proliferation. Kyoto Encyclopedia of Genes and Genomes pathway analysis demonstrated that Hippo, Wnt, transforming growth factor-beta, and Hedgehog signaling pathv/ays were potentially associated with neural differentiation of b展开更多
The greatest challenge to successful treatment of spinal cord injury is the limited regenerative capacity of the central nervous system and its inability to replace lost neurons and severed axons following injury. Neu...The greatest challenge to successful treatment of spinal cord injury is the limited regenerative capacity of the central nervous system and its inability to replace lost neurons and severed axons following injury. Neural stem cell grafts derived from fetal central nervous system tissue or embryonic stem cells have shown therapeutic promise by differentiation into neurons and glia that have the potential to form functional neuronal relays across injured spinal cord segments. However, implementation of fetal-derived or embryonic stem cell-derived neural stem cell ther- apies for patients with spinal cord injury raises ethical concerns. Induced pluripotent stem cells can be generated from adult somatic cells and differentiated into neural stem cells suitable for therapeutic use, thereby providing an ethical source of implantable cells that can be made in an autologous fashion to avoid problems of immune rejection. This review discusses the therapeutic potential of human induced pluripotent stem cell-derived neural stem cell transplantation for treatment of spinal cord injury, as well as addressing potential mechanisms, future perspectives and challenges.展开更多
Pluripotent stem cells, which are capable of differentiating in various species of cells, are hoped to be donor cells in transplantation in regenerative medicine. Embryonic stem(ES) cells and induced pluripotent stem ...Pluripotent stem cells, which are capable of differentiating in various species of cells, are hoped to be donor cells in transplantation in regenerative medicine. Embryonic stem(ES) cells and induced pluripotent stem cells have the potential to differentiate in approximately all species of cells. However, the proliferating ability of these cells is high and the cancer formation ability is also recognized. In addition, ethical problems exist in using ES cells. Somatic stem cells with the ability to differentiate in various species of cells have been used as donor cells for neuronal diseases, such as amyotrophic lateral sclerosis, spinal cord injury, Alzheimer disease,cerebral infarction and congenital neuronal diseases.Human mesenchymal stem cells derived from bone marrow, adipose tissue, dermal tissue, umbilical cord blood and placenta are usually used for intractable neuronal diseases as somatic stem cells, while neural progenitor/stem cells and retinal progenitor/stem cells are used for a few congenital neuronal diseases and retinal degenerative disease, respectively. However,non-treated somatic stem cells seldom differentiate to neural cells in recipient neural tissue. Therefore, the contribution to neuronal regeneration using non-treated somatic stem cells has been poor and various differential trials, such as the addition of neurotrophic factors,gene transfer, peptide transfer for neuronal differentiation of somatic stem cells, have been performed. Here,the recent progress of regenerative therapies using various somatic stem cells is described.展开更多
Classical methyl-CpG binding proteins contain the conserved DNA binding motif methyl-cytosine binding domain(MBD), which preferentially binds to methylated CpG dinucleotides. These proteins serve as transcriptional re...Classical methyl-CpG binding proteins contain the conserved DNA binding motif methyl-cytosine binding domain(MBD), which preferentially binds to methylated CpG dinucleotides. These proteins serve as transcriptional repressors,mediating gene silencing via DNA cytosine methylation. Mutations in methyl-CpG binding protein 2 (MeCP2) have beenlinked to the human mental retardation disorder Rett syndrome, suggesting an important role for methyl-CpG bindingproteins in brain development and function. This mini-review summarizes the recent advances in studying the diversefunctions of MeCP2 as a prototype for other methyl-CpG binding proteins in the development and function of thevertebrate nervous system.展开更多
BACKGROUND： Multipotent adult progenitor cells （MAPCs） from the bone marrow have been shown to differentiate into neurons. OBJECTIVE： To observe migration, survival, and neuronal-like differentiation of MAPCs by t...BACKGROUND： Multipotent adult progenitor cells （MAPCs） from the bone marrow have been shown to differentiate into neurons. OBJECTIVE： To observe migration, survival, and neuronal-like differentiation of MAPCs by tail vein injection. DESIGN, TIME AND SETTING： Randomized, controlled experiment of neural tissue engineering was performed at the Laboratory for Cardio-Cerebrovascular Disease, Hospital of Integrated Traditional and Western Medicine, Tongji Medical College of Huazhong University of Science and Technology between September 2006 and August 2007. MATERIALS： Eighty Sprague Dawley rats, 3-6 months old, underwent cerebral ischemia/reperfusion by thread technique, and were randomly divided into model and MAPCs groups （n = 40）. METHODS： Mononuclear cells were harvested from bone marrow using the FicolI-Paque density gradient centrifugation method. After removing CD45 and glycophorin A-positive cells （GLYA＋） with immunomagnetic beads, CD45 GLYA adult progenitor cells were labeled with bromodeoxyuridine （5-bromo-2-deoxyuridine, BrdU）. A total of 1 mL cell suspension, containing 5 × 10^6 MAPCs, was injected into the MAPCs group through the tail vein. A total of 1 mL normal saline was injected into the model rats. MAIN OUTCOME MEASURES： After 60 days, BrdU and neuron-specific enolase double-positive cells were observed using immunofluorescence. Cell morphology was observed under electron microscopy, and nerve growth factor mRNA was measured through RT-PCR. In addition, rat neurological functions were measured with behavioral tests. RESULTS： Immunofluorescence revealed that MAPCs positive for BrdU and neuron specific enolase were found surrounding the ischemic focus in the MAPCs group. Microscopic observation suggested that MAPCs-derived neuronal-like cells connected with other nerve cells to form synapses. Compared with the model animals, the level of nerve growth factor mRNA was significantly upregulated in rats injected with MAPCs （P 〈 0.05）. In addition, rats in the MAPCs gr展开更多
Extracellular matrix(ECM)influences cell differentiation through its structural and biochemical properties.In nervous system,neuronal behavior is influenced by these ECMs structures which are present in a meshwork,fib...Extracellular matrix(ECM)influences cell differentiation through its structural and biochemical properties.In nervous system,neuronal behavior is influenced by these ECMs structures which are present in a meshwork,fibrous,or tubular forms encompassing specific molecular compositions.In addition to contact guidance,ECM composition and structures also exert its effect on neuronal differentiation.This short report reviewed the native ECM structure and composition in central nervous system and peripheral nervous system,and their impact on neural regeneration and neuronal differentiation.Using topographies,stem cells have been differentiated to neurons.Further,focussing on engineered biomimicking topographies,we highlighted the role of anisotropic topographies in stem cell differentiation to neurons and its recent temporal application for efficient neuronal differentiation.展开更多
Nuclear factor Y is a ubiquitous heterotrimeric transcription factor complex conserved across eukaryotes that binds to CCAAT boxes,one of the most common motifs found in gene promoters and enhancers.Over the last 30 y...Nuclear factor Y is a ubiquitous heterotrimeric transcription factor complex conserved across eukaryotes that binds to CCAAT boxes,one of the most common motifs found in gene promoters and enhancers.Over the last 30 years,research has revealed that the nuclear factor Y complex controls many aspects of brain development,including differentiation,axon guidance,homeostasis,disease,and most recently regeneration.However,a complete understanding of transcriptional regulatory networks,including how the nuclear factor Y complex binds to specific CCAAT boxes to perform its function remains elusive.In this review,we explore the nuclear factor Y complex’s role and mode of action during brain development,as well as how genomic technologies may expand understanding of this key regulator of gene expression.展开更多
Cell replacement therapy utilizing mesenchymal stem cells as its main resource holds great promise for ultimate treatment of human neurological disorders.Parkinson＇s disease（PD）is a common,chronic neurodegenerative...Cell replacement therapy utilizing mesenchymal stem cells as its main resource holds great promise for ultimate treatment of human neurological disorders.Parkinson＇s disease（PD）is a common,chronic neurodegenerative disorder hallmarked by localized degeneration of a specific set of dopaminergic neurons within a midbrain sub-region.The specific cell type and confined location of degenerating neurons make cell replacement therapy ideal for PD treatment since it mainly requires replenishment of lost dopaminergic neurons with fresh and functional ones.Endogenous as well as exogenous cell sources have been identified as candidate targets for cell replacement therapy in PD.In this review,umbilical cord mesenchymal stem cells（UCMSCs）are discussed as they provide an inexpensive unlimited reservoir differentiable towards functional dopaminergic neurons that potentially lead to long-lasting behavioral recovery in PD patients.We also present mi RNAs-mediated neuronal differentiation of UCMSCs.The UCMSCs bear a number of outstanding characteristics including their non-tumorigenic,low-immunogenic properties that make them ideal for cell replacement therapy purposes.Nevertheless,more investigations as well as controlled clinical trials are required to thoroughly confirm the efficacy of UCMSCs for therapeutic medical-grade applications in PD.展开更多
Direct reprogramming of a variety of somatic cells with the transcription factors Oct4(also called Pou5f1),Sox2 with either Klf4 and Myc or Lin28 and Nanog generates the induced pluripotent stem cells(iPSCs)with marke...Direct reprogramming of a variety of somatic cells with the transcription factors Oct4(also called Pou5f1),Sox2 with either Klf4 and Myc or Lin28 and Nanog generates the induced pluripotent stem cells(iPSCs)with marker similarity to embryonic stem cells.However,the difference between iPSCs derived from different origins is unclear.In this study,we hypothesized that reprogrammed cells retain a“memory”of their origins and possess additional potential of related tissue differentiation.We reprogrammed primary mouse astrocytes via ectopic retroviral expression of OCT3/4,Sox2,Klf4 and Myc and found the iPSCs from mouse astrocytes expressed stem cell markers and formed teratomas in SCID mice containing derivatives of all three germ layers similar to mouse embryonic stem cells besides semblable morphologies.To test our hypothesis,we compared embryonic bodies(EBs)formation and neuronal differentiation between iPSCs from mouse embryonic fibroblasts(MEFsiPSCs)and iPSCs from mouse astrocytes(mAsiPSCs).We found that mAsiPSCs grew slower and possessed more potential for neuronal differentiation compared to MEFsiPSCs.Our results suggest that mAsiPSCs retain a“memory”of the central nervous system,which confers additional potential upon neuronal differentiation.展开更多
基金This work was funded by the Chinese National Natural Science Foundation （No. 81071009 and No. 81271412）, International S＆T Cooperation Project of the Ministry of S＆T of China （No. 2010DFR30850）, People＇s Livelihood S＆T Project, Bureau of S＆T of Dalian （Nos. 2010E 11SF008 and 2011E 12SF030）, and Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry.
文摘Background In order to suggest an ideal source of adult stem cells for the treatment of nervous system diseases,MSCs from human adipose tissue and bone marrow were isolated and studied to explore the differences with regard to cell morphology,surface markers,neuronal differentiation capacity,especially the synapse structure formation and the secretion of neurotrophic factors.Methods The neuronal differentiation capacity of human mesenchymal stem cells from adipose tissue （hADSCs） and bone marrow （hBMSCs） was determined based on nissl body and synapse structure formation,and neural factor secretion function.hADSCs and hBMSCs were isolated and differentiated into neuron-like cells with rat brain-conditioned medium,a potentially rich source of neuronal differentiation promoting signals.Specific neuronal proteins and neural factors were detected by immunohistochemistry and enzyme-linked immunosorbent assay analysis,respectively.Results Flow cytometric analysis showed that both cell types had similar phenotypes.Cell growth curves showed that hADSCs proliferated more quickly than hBMSCs.Both kinds of cells were capable of osteogenic and adipogenic differentiation.The morphology of hADSCs and hBMSCs changed during neuronal differentiation and displayed neuronlike cell appearance after 14 days＇ differentiation.Both hADSCs and hBMSCs were able to differentiate into neuron-like cells based on their production of neuron specific proteins including β-tubulin-Ⅲ,neuron-specific enolase （NSE）,nissl bodies,and their ability to secrete brain derived neurotrophic factor （BDNF） and nerve growth factor （NGF）.Assessment of synaptop hysin and growth-associated protein-43 （GAP-43） suggested synapse structure formation in differentiated hADSCs and hBMSCs.Conclusions Our results demonstrate that hADSCs have neuronal differentiation potential similar to hBMSC,but with a higher proliferation capacity than hBMSC.Adipose tissue is abundant,easily available and would be a potential ideal source of adult stem cells
文摘MicroRNAs play important roles in post-transcriptional regulation of gene expression by inhibiting protein translation and/or promoting mRNA degradation.Importantly,biogenesis of microRNAs displays specific temporal and spatial profiles in distinct cell and tissue types and hence affects a broad spectrum of biological functions in normal cell growth and tumor development.Recent discoveries have revealed sophisticated mechanisms that control microRNA production and homeostasis in response to developmental and extracellular signals.Moreover,a link between dysregulation of microRNAs and human brain disorders has become increasingly evident.In this review,we focus on recent advances in understanding the regulation of microRNA biogenesis and function in neuronal and glial development in the mammalian brain,and dysregulation of the microRNA pathway in neurodevelopmental and neurodegenerative diseases.
文摘Recent studies have identified mutations in PHF8, an X-linked gene encoding a JmjC domain-containing protein, as a causal factor for X-linked mental retardation （XLMR） and cleft lip/cleft palate. However, the underlying mechanism is unknown. Here we show that PHF8 is a histone demethylase and coactivator for retinoic acid receptor （RAR）. Although activities for both H3K4me3/2/1 and H3K9me2/1 demethylation were detected in cellularbased assays, reeombinant PHF8 exhibited only H3K9me2/1 demethylase activity in vitro, suggesting that PHF8 is an H3K9me2/1 demethylase whose specificity may be modulated in vivo. Importantly, a mutant PHF8 （phenylalanine at position 279 to serine） identified in the XLMR patients is defective in enzymatie activity, indicating that the loss of histone demethylase activity is causally linked with the onset of disease. In addition, we show that PHF8 binds specifically to H3K4me3/2 peptides via an N-terminal PHD finger domain. Consistent with a role for PHF8 in neuronal differentiation, knockdown of PHF8 in mouse embryonic carcinoma P19 cells impairs RA-induced neuronal differentiation, whereas overexpression of the wild-type but not the F279S mutant PHF8 drives PI9 cells toward neuronal differentiation. Furthermore, we show that PHF8 interacts with RAR~ and functions as a coactivator for RARa. Taken together, our results suggest that histone methylation modulated by PHF8 plays a critical role in neuronal differentiation.
基金supported by the National Natural Science Foundation of China,No.81330042,81620108018(both to SQF),and 81702147(to ZJW)
文摘Bone marrow-derived mesenchymal stem cells differentiate into neurons under the induction of Schwann cells. However, key microRNAs and related pathways for differentiation remain unclear. This study screened and identified differentially expressed microRNAs in bone marrow- derived mesenchymal stem cells induced by Schwann cell-conditioned medium, and explored targets and related pathways involved in their differentiation into neuronal-like cells. Primary bone marrow-derived mesenchymal stem cells were isolated from femoral and tibial bones, while primary Schwann cells were isolated from bilateral saphenous nerves. Bone marrow-derived mesenchymal stem cells were cultured in unconditioned (control group) and Schwann cell-conditioned medium (bone marrow-derived mesenchymal stem cell + Schwann cell group). Neuronal differentiation of bone marrow-derived mesenchymal stem cells induced by Schwann cell-conditioned medium was observed by time-lapse imaging. Upon induction, the morphology of bone marrow-derived mesencaymal stem cells changed into a neural shape with neurites. Results of quantitative reverse transcription-polymerase chain reaction revealed that nestin mRNA expression was upregulated from 1 to 3 days and downregulated from 3 to 7 days in the bone marrow-derived mesenchymal stem cell + Schwann cell group. Compared with the control group, microtubule-associated protein 2 mRNA expression gradually increased from 1 to 7 days in the bone marrow-derived mesenchymal stem cell + Schwann cell group. After 7 days of induction, microRNA analysis iden:ified 83 significantly differentially expressed microRNAs between the two groups. Gene Ontology analysis indicated enrichment of microRNA target genes for neuronal projection development, regulation of axonogenesis, and positive regulation of cell proliferation. Kyoto Encyclopedia of Genes and Genomes pathway analysis demonstrated that Hippo, Wnt, transforming growth factor-beta, and Hedgehog signaling pathv/ays were potentially associated with neural differentiation of b
基金supported by grants from the Veterans Administration and the California Institute for Regenerative Medicine
文摘The greatest challenge to successful treatment of spinal cord injury is the limited regenerative capacity of the central nervous system and its inability to replace lost neurons and severed axons following injury. Neural stem cell grafts derived from fetal central nervous system tissue or embryonic stem cells have shown therapeutic promise by differentiation into neurons and glia that have the potential to form functional neuronal relays across injured spinal cord segments. However, implementation of fetal-derived or embryonic stem cell-derived neural stem cell ther- apies for patients with spinal cord injury raises ethical concerns. Induced pluripotent stem cells can be generated from adult somatic cells and differentiated into neural stem cells suitable for therapeutic use, thereby providing an ethical source of implantable cells that can be made in an autologous fashion to avoid problems of immune rejection. This review discusses the therapeutic potential of human induced pluripotent stem cell-derived neural stem cell transplantation for treatment of spinal cord injury, as well as addressing potential mechanisms, future perspectives and challenges.
文摘Pluripotent stem cells, which are capable of differentiating in various species of cells, are hoped to be donor cells in transplantation in regenerative medicine. Embryonic stem(ES) cells and induced pluripotent stem cells have the potential to differentiate in approximately all species of cells. However, the proliferating ability of these cells is high and the cancer formation ability is also recognized. In addition, ethical problems exist in using ES cells. Somatic stem cells with the ability to differentiate in various species of cells have been used as donor cells for neuronal diseases, such as amyotrophic lateral sclerosis, spinal cord injury, Alzheimer disease,cerebral infarction and congenital neuronal diseases.Human mesenchymal stem cells derived from bone marrow, adipose tissue, dermal tissue, umbilical cord blood and placenta are usually used for intractable neuronal diseases as somatic stem cells, while neural progenitor/stem cells and retinal progenitor/stem cells are used for a few congenital neuronal diseases and retinal degenerative disease, respectively. However,non-treated somatic stem cells seldom differentiate to neural cells in recipient neural tissue. Therefore, the contribution to neuronal regeneration using non-treated somatic stem cells has been poor and various differential trials, such as the addition of neurotrophic factors,gene transfer, peptide transfer for neuronal differentiation of somatic stem cells, have been performed. Here,the recent progress of regenerative therapies using various somatic stem cells is described.
文摘Classical methyl-CpG binding proteins contain the conserved DNA binding motif methyl-cytosine binding domain(MBD), which preferentially binds to methylated CpG dinucleotides. These proteins serve as transcriptional repressors,mediating gene silencing via DNA cytosine methylation. Mutations in methyl-CpG binding protein 2 (MeCP2) have beenlinked to the human mental retardation disorder Rett syndrome, suggesting an important role for methyl-CpG bindingproteins in brain development and function. This mini-review summarizes the recent advances in studying the diversefunctions of MeCP2 as a prototype for other methyl-CpG binding proteins in the development and function of thevertebrate nervous system.
文摘BACKGROUND： Multipotent adult progenitor cells （MAPCs） from the bone marrow have been shown to differentiate into neurons. OBJECTIVE： To observe migration, survival, and neuronal-like differentiation of MAPCs by tail vein injection. DESIGN, TIME AND SETTING： Randomized, controlled experiment of neural tissue engineering was performed at the Laboratory for Cardio-Cerebrovascular Disease, Hospital of Integrated Traditional and Western Medicine, Tongji Medical College of Huazhong University of Science and Technology between September 2006 and August 2007. MATERIALS： Eighty Sprague Dawley rats, 3-6 months old, underwent cerebral ischemia/reperfusion by thread technique, and were randomly divided into model and MAPCs groups （n = 40）. METHODS： Mononuclear cells were harvested from bone marrow using the FicolI-Paque density gradient centrifugation method. After removing CD45 and glycophorin A-positive cells （GLYA＋） with immunomagnetic beads, CD45 GLYA adult progenitor cells were labeled with bromodeoxyuridine （5-bromo-2-deoxyuridine, BrdU）. A total of 1 mL cell suspension, containing 5 × 10^6 MAPCs, was injected into the MAPCs group through the tail vein. A total of 1 mL normal saline was injected into the model rats. MAIN OUTCOME MEASURES： After 60 days, BrdU and neuron-specific enolase double-positive cells were observed using immunofluorescence. Cell morphology was observed under electron microscopy, and nerve growth factor mRNA was measured through RT-PCR. In addition, rat neurological functions were measured with behavioral tests. RESULTS： Immunofluorescence revealed that MAPCs positive for BrdU and neuron specific enolase were found surrounding the ischemic focus in the MAPCs group. Microscopic observation suggested that MAPCs-derived neuronal-like cells connected with other nerve cells to form synapses. Compared with the model animals, the level of nerve growth factor mRNA was significantly upregulated in rats injected with MAPCs （P 〈 0.05）. In addition, rats in the MAPCs gr
基金supported by the Natural Sciences and Engineering Research Council of Canada(NSERC) Discovery(NSERC 2016040 to DJ,SM and EKFY)+4 种基金University of Waterloo start up fund(to DJ,SM and EKFY) for their generous fundingNSERC Undergraduate Student Research Awards(USRAto SM and EKFY)Collaborative Research and Training Experience(CREATE,401207296to SM and EKFY) for their generous partial funding
文摘Extracellular matrix(ECM)influences cell differentiation through its structural and biochemical properties.In nervous system,neuronal behavior is influenced by these ECMs structures which are present in a meshwork,fibrous,or tubular forms encompassing specific molecular compositions.In addition to contact guidance,ECM composition and structures also exert its effect on neuronal differentiation.This short report reviewed the native ECM structure and composition in central nervous system and peripheral nervous system,and their impact on neural regeneration and neuronal differentiation.Using topographies,stem cells have been differentiated to neurons.Further,focussing on engineered biomimicking topographies,we highlighted the role of anisotropic topographies in stem cell differentiation to neurons and its recent temporal application for efficient neuronal differentiation.
基金supported by National Health and Medical Research Council GNT1105374,GNT1137645,GNT2000766 and veski Innovation Fellowship(VIF23)to RP.
文摘Nuclear factor Y is a ubiquitous heterotrimeric transcription factor complex conserved across eukaryotes that binds to CCAAT boxes,one of the most common motifs found in gene promoters and enhancers.Over the last 30 years,research has revealed that the nuclear factor Y complex controls many aspects of brain development,including differentiation,axon guidance,homeostasis,disease,and most recently regeneration.However,a complete understanding of transcriptional regulatory networks,including how the nuclear factor Y complex binds to specific CCAAT boxes to perform its function remains elusive.In this review,we explore the nuclear factor Y complex’s role and mode of action during brain development,as well as how genomic technologies may expand understanding of this key regulator of gene expression.
文摘Cell replacement therapy utilizing mesenchymal stem cells as its main resource holds great promise for ultimate treatment of human neurological disorders.Parkinson＇s disease（PD）is a common,chronic neurodegenerative disorder hallmarked by localized degeneration of a specific set of dopaminergic neurons within a midbrain sub-region.The specific cell type and confined location of degenerating neurons make cell replacement therapy ideal for PD treatment since it mainly requires replenishment of lost dopaminergic neurons with fresh and functional ones.Endogenous as well as exogenous cell sources have been identified as candidate targets for cell replacement therapy in PD.In this review,umbilical cord mesenchymal stem cells（UCMSCs）are discussed as they provide an inexpensive unlimited reservoir differentiable towards functional dopaminergic neurons that potentially lead to long-lasting behavioral recovery in PD patients.We also present mi RNAs-mediated neuronal differentiation of UCMSCs.The UCMSCs bear a number of outstanding characteristics including their non-tumorigenic,low-immunogenic properties that make them ideal for cell replacement therapy purposes.Nevertheless,more investigations as well as controlled clinical trials are required to thoroughly confirm the efficacy of UCMSCs for therapeutic medical-grade applications in PD.
基金the National Institutes of Health:R01 NS 41858-01,R01 NS 061642-01,R21 MH 083525-01,P01 NS043985,and P20 RR15635-01(JZ)the State of Nebraska,DHHS-LB606(JZ),Stem Cell-2010-10(SD)National Natural Science Foundation of China(Grant No.81028007)(JZ).
文摘Direct reprogramming of a variety of somatic cells with the transcription factors Oct4(also called Pou5f1),Sox2 with either Klf4 and Myc or Lin28 and Nanog generates the induced pluripotent stem cells(iPSCs)with marker similarity to embryonic stem cells.However,the difference between iPSCs derived from different origins is unclear.In this study,we hypothesized that reprogrammed cells retain a“memory”of their origins and possess additional potential of related tissue differentiation.We reprogrammed primary mouse astrocytes via ectopic retroviral expression of OCT3/4,Sox2,Klf4 and Myc and found the iPSCs from mouse astrocytes expressed stem cell markers and formed teratomas in SCID mice containing derivatives of all three germ layers similar to mouse embryonic stem cells besides semblable morphologies.To test our hypothesis,we compared embryonic bodies(EBs)formation and neuronal differentiation between iPSCs from mouse embryonic fibroblasts(MEFsiPSCs)and iPSCs from mouse astrocytes(mAsiPSCs).We found that mAsiPSCs grew slower and possessed more potential for neuronal differentiation compared to MEFsiPSCs.Our results suggest that mAsiPSCs retain a“memory”of the central nervous system,which confers additional potential upon neuronal differentiation.
