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Reprogramming cells for brain repair.

Guarino AT, McKinnon RD - Brain Sci (2013)

Bottom Line: While redundancy and rewiring of surviving circuits can recover some lost function, the brain and spinal column lack sufficient endogenous stem cells to replace lost neurons or their supporting glia.In contrast, pre-clinical studies have demonstrated that exogenous transplants can have remarkable efficacy for brain repair in animal models.The cell reprogramming field has developed the ability to trans-differentiate somatic cells into distinct cell types, a technology that has the potential to generate autologous neurons and glia which address the histocompatibility concerns of allografts and the tumorigenicity concerns of ESC-derived grafts.

View Article: PubMed Central - PubMed

Affiliation: Neurosurgery, Rutgers-Robert Wood Johnson Medical School, 125 Patterson St. CAB 7084, New Brunswick, NJ 08903, USA. aguarino@eden.rutgers.edu.

ABSTRACT
At present there are no clinical therapies that can repair traumatic brain injury, spinal cord injury or degenerative brain disease. While redundancy and rewiring of surviving circuits can recover some lost function, the brain and spinal column lack sufficient endogenous stem cells to replace lost neurons or their supporting glia. In contrast, pre-clinical studies have demonstrated that exogenous transplants can have remarkable efficacy for brain repair in animal models. Mesenchymal stromal cells (MSCs) can provide paracrine factors that repair damage caused by ischemic injury, and oligodendrocyte progenitor cell (OPC) grafts give dramatic functional recovery from spinal cord injury. These studies have progressed to clinical trials, including human embryonic stem cell (hESC)-derived OPCs for spinal cord repair. However, ESC-derived allografts are less than optimal, and we need to identify a more appropriate donor graft population. The cell reprogramming field has developed the ability to trans-differentiate somatic cells into distinct cell types, a technology that has the potential to generate autologous neurons and glia which address the histocompatibility concerns of allografts and the tumorigenicity concerns of ESC-derived grafts. Further clarifying how cell reprogramming works may lead to more efficient direct reprogram approaches, and possibly in vivo reprogramming, in order to promote brain and spinal cord repair.

No MeSH data available.


Related in: MedlinePlus

On, off, and poised loci. (A) Oct3/4, Sox2 and Nanog positively regulate genes necessary for pluripotency and self renewal in ES cells; (B) ES cells also silence genes in order to remain pluripotent; Oct3/4 coordinates CpG DNA methylation and H3K9 histone methylation via DNA methyltransferase and sumoylated SetDB1; (C) H2A-K119 ubiquitination by PRC1 is necessary for RNA Polymerase (PolII) to maintain bivalent genes poised for activation.
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brainsci-03-01215-f002: On, off, and poised loci. (A) Oct3/4, Sox2 and Nanog positively regulate genes necessary for pluripotency and self renewal in ES cells; (B) ES cells also silence genes in order to remain pluripotent; Oct3/4 coordinates CpG DNA methylation and H3K9 histone methylation via DNA methyltransferase and sumoylated SetDB1; (C) H2A-K119 ubiquitination by PRC1 is necessary for RNA Polymerase (PolII) to maintain bivalent genes poised for activation.

Mentions: iPS reprogramming requires suppression of the fibroblast transcriptome and activation of ESC-specific genes, and reprogramming fibroblasts into iPS cells serves as a model for understanding how cell identity is maintained and revised. The ESC master regulators Oct4, Sox2 and Nanog [71,72,73] coordinately regulate 353 known genes to control ESC identity [74]. These include micro-RNAs (miRNAs) that are important for ESC pluripotency and differentiation [75] and have a role in Dicer-targeted destruction of ESC-specific mRNAs during differentiation [76]. They also regulate their own promoters in a positive-feedback loop to promote the undifferentiated state. ESCs differentiate to trophectoderm when Oct4 levels are below 50%, into primitive endoderm and mesoderm when Oct4 is above 150% of wild-type [77], or into endoderm and trophectoderm in the absence of Nanog [78]. These factors bind to cis-regulatory DNA sites and recruit chromatin interacting co-factors [79] and RNA Pol II [75] to activate gene expression (Figure 2A). Oct4 can also repress genes (Figure 2B) such as the trophectoderm factor Cdx2 [75,80] which, if expressed, can feed back to repress pluripotency genes. Mechanisms that maintain transcriptionally silent heterochromatin include epigenetic chromatin marks such as DNA methylation and histone modifications (methylation, acetylation) and histone variant exchange.The Oct4 SUMO-interacting motif (SIM) recruits a histone methyltransferase (SUMOylated ESET) which methylates histone H3 on specific lysines (H3K9) to repress Cdx2 expression [80]. Other repressive modifications are generated by the Polycomb Repressive Complex (PRC) [81] including H2A mono-ubiquination by PRC1 and H3 tri-methylation by PRC2 [82]. PRC1 can also maintain a subset of genes in a silenced but actionable “bivalent” state (Figure 2C) and recruit RNA PolII to these genes via H2A ubiquitination [75,83].


Reprogramming cells for brain repair.

Guarino AT, McKinnon RD - Brain Sci (2013)

On, off, and poised loci. (A) Oct3/4, Sox2 and Nanog positively regulate genes necessary for pluripotency and self renewal in ES cells; (B) ES cells also silence genes in order to remain pluripotent; Oct3/4 coordinates CpG DNA methylation and H3K9 histone methylation via DNA methyltransferase and sumoylated SetDB1; (C) H2A-K119 ubiquitination by PRC1 is necessary for RNA Polymerase (PolII) to maintain bivalent genes poised for activation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061879&req=5

brainsci-03-01215-f002: On, off, and poised loci. (A) Oct3/4, Sox2 and Nanog positively regulate genes necessary for pluripotency and self renewal in ES cells; (B) ES cells also silence genes in order to remain pluripotent; Oct3/4 coordinates CpG DNA methylation and H3K9 histone methylation via DNA methyltransferase and sumoylated SetDB1; (C) H2A-K119 ubiquitination by PRC1 is necessary for RNA Polymerase (PolII) to maintain bivalent genes poised for activation.
Mentions: iPS reprogramming requires suppression of the fibroblast transcriptome and activation of ESC-specific genes, and reprogramming fibroblasts into iPS cells serves as a model for understanding how cell identity is maintained and revised. The ESC master regulators Oct4, Sox2 and Nanog [71,72,73] coordinately regulate 353 known genes to control ESC identity [74]. These include micro-RNAs (miRNAs) that are important for ESC pluripotency and differentiation [75] and have a role in Dicer-targeted destruction of ESC-specific mRNAs during differentiation [76]. They also regulate their own promoters in a positive-feedback loop to promote the undifferentiated state. ESCs differentiate to trophectoderm when Oct4 levels are below 50%, into primitive endoderm and mesoderm when Oct4 is above 150% of wild-type [77], or into endoderm and trophectoderm in the absence of Nanog [78]. These factors bind to cis-regulatory DNA sites and recruit chromatin interacting co-factors [79] and RNA Pol II [75] to activate gene expression (Figure 2A). Oct4 can also repress genes (Figure 2B) such as the trophectoderm factor Cdx2 [75,80] which, if expressed, can feed back to repress pluripotency genes. Mechanisms that maintain transcriptionally silent heterochromatin include epigenetic chromatin marks such as DNA methylation and histone modifications (methylation, acetylation) and histone variant exchange.The Oct4 SUMO-interacting motif (SIM) recruits a histone methyltransferase (SUMOylated ESET) which methylates histone H3 on specific lysines (H3K9) to repress Cdx2 expression [80]. Other repressive modifications are generated by the Polycomb Repressive Complex (PRC) [81] including H2A mono-ubiquination by PRC1 and H3 tri-methylation by PRC2 [82]. PRC1 can also maintain a subset of genes in a silenced but actionable “bivalent” state (Figure 2C) and recruit RNA PolII to these genes via H2A ubiquitination [75,83].

Bottom Line: While redundancy and rewiring of surviving circuits can recover some lost function, the brain and spinal column lack sufficient endogenous stem cells to replace lost neurons or their supporting glia.In contrast, pre-clinical studies have demonstrated that exogenous transplants can have remarkable efficacy for brain repair in animal models.The cell reprogramming field has developed the ability to trans-differentiate somatic cells into distinct cell types, a technology that has the potential to generate autologous neurons and glia which address the histocompatibility concerns of allografts and the tumorigenicity concerns of ESC-derived grafts.

View Article: PubMed Central - PubMed

Affiliation: Neurosurgery, Rutgers-Robert Wood Johnson Medical School, 125 Patterson St. CAB 7084, New Brunswick, NJ 08903, USA. aguarino@eden.rutgers.edu.

ABSTRACT
At present there are no clinical therapies that can repair traumatic brain injury, spinal cord injury or degenerative brain disease. While redundancy and rewiring of surviving circuits can recover some lost function, the brain and spinal column lack sufficient endogenous stem cells to replace lost neurons or their supporting glia. In contrast, pre-clinical studies have demonstrated that exogenous transplants can have remarkable efficacy for brain repair in animal models. Mesenchymal stromal cells (MSCs) can provide paracrine factors that repair damage caused by ischemic injury, and oligodendrocyte progenitor cell (OPC) grafts give dramatic functional recovery from spinal cord injury. These studies have progressed to clinical trials, including human embryonic stem cell (hESC)-derived OPCs for spinal cord repair. However, ESC-derived allografts are less than optimal, and we need to identify a more appropriate donor graft population. The cell reprogramming field has developed the ability to trans-differentiate somatic cells into distinct cell types, a technology that has the potential to generate autologous neurons and glia which address the histocompatibility concerns of allografts and the tumorigenicity concerns of ESC-derived grafts. Further clarifying how cell reprogramming works may lead to more efficient direct reprogram approaches, and possibly in vivo reprogramming, in order to promote brain and spinal cord repair.

No MeSH data available.


Related in: MedlinePlus