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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

oligodendrocyte progenitor cell (OPC) resources for brain and spinal cord grafts. 1983: OPCs were first characterized in rodents [7]; OPCs were first grafted into shiverer mice [5]; 1999: OPCs generated by in vitro differentiation of mouse blastocyst-derived embryonic stem cells (ESCs) [16]; 2005: OPCs used to repair spinal cord injured rats [17]. 2006: human OPCs generated from induced pluripotent stem (iPS) cells [18]; 2010: human ES-derived OPCs first used in clinical trials; 2013: murine OPCs generated by direct cell reprogramming [19,20].
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brainsci-03-01215-f001: oligodendrocyte progenitor cell (OPC) resources for brain and spinal cord grafts. 1983: OPCs were first characterized in rodents [7]; OPCs were first grafted into shiverer mice [5]; 1999: OPCs generated by in vitro differentiation of mouse blastocyst-derived embryonic stem cells (ESCs) [16]; 2005: OPCs used to repair spinal cord injured rats [17]. 2006: human OPCs generated from induced pluripotent stem (iPS) cells [18]; 2010: human ES-derived OPCs first used in clinical trials; 2013: murine OPCs generated by direct cell reprogramming [19,20].

Mentions: The myelin field pioneered neural cell transplants and demonstrated repair in a variety of animal models including developmental defects, myelin destruction from injury (viral pathogens, chemical toxins), and autoimmune demyelination models of MS (experimental allergic encephalomyelitis). The consensus from these studies is that mitotic and mobile oligodendrocyte progenitor cells (OPCs) are the optimal graft cell population and that immune suppression with steroids or adjunctive MSC is necessary. Early studies from Dr. Gumpel’s group [5] grafted rodent then human brain tissue into shiverer (shi) mice. Shi mice lack the myelin basic protein gene [6]; their non-compacted CNS myelin degenerates (dys-myelination) and they develop movement-stimulated tremors by two weeks and die at 3–4 months due to sleep apnea. While it does not mimic the autoimmune demyelination of MS, this model facilitates an analysis of the remyelinating ability of transplant derived OLs. Recent advances in this field (Figure 1) came after the characterization of OPCs from the neonatal rat brain [7] and ligands that control OPC proliferation, differentiation and survival in vitro [8,9]. This allowed the amplification and transplant of pure OPCs populations [10], identification of the optimal maturation stage for myelination [11] and ultimately the rescue of the Shi motor phenotype and lethality [12,13,14]. The Shi mouse model is now a graft-curable genetic lethal disease, and Shi mice have been used to estimate the minimal number of wild-type cells necessary for functional rescue (7% graft chimerism) [13]. This may represent an upper limit, as co-transplants with adjunctive MSCs improves the survival of transplanted OPCs [15].


Reprogramming cells for brain repair.

Guarino AT, McKinnon RD - Brain Sci (2013)

oligodendrocyte progenitor cell (OPC) resources for brain and spinal cord grafts. 1983: OPCs were first characterized in rodents [7]; OPCs were first grafted into shiverer mice [5]; 1999: OPCs generated by in vitro differentiation of mouse blastocyst-derived embryonic stem cells (ESCs) [16]; 2005: OPCs used to repair spinal cord injured rats [17]. 2006: human OPCs generated from induced pluripotent stem (iPS) cells [18]; 2010: human ES-derived OPCs first used in clinical trials; 2013: murine OPCs generated by direct cell reprogramming [19,20].
© Copyright Policy - open-access
Related In: Results  -  Collection

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

brainsci-03-01215-f001: oligodendrocyte progenitor cell (OPC) resources for brain and spinal cord grafts. 1983: OPCs were first characterized in rodents [7]; OPCs were first grafted into shiverer mice [5]; 1999: OPCs generated by in vitro differentiation of mouse blastocyst-derived embryonic stem cells (ESCs) [16]; 2005: OPCs used to repair spinal cord injured rats [17]. 2006: human OPCs generated from induced pluripotent stem (iPS) cells [18]; 2010: human ES-derived OPCs first used in clinical trials; 2013: murine OPCs generated by direct cell reprogramming [19,20].
Mentions: The myelin field pioneered neural cell transplants and demonstrated repair in a variety of animal models including developmental defects, myelin destruction from injury (viral pathogens, chemical toxins), and autoimmune demyelination models of MS (experimental allergic encephalomyelitis). The consensus from these studies is that mitotic and mobile oligodendrocyte progenitor cells (OPCs) are the optimal graft cell population and that immune suppression with steroids or adjunctive MSC is necessary. Early studies from Dr. Gumpel’s group [5] grafted rodent then human brain tissue into shiverer (shi) mice. Shi mice lack the myelin basic protein gene [6]; their non-compacted CNS myelin degenerates (dys-myelination) and they develop movement-stimulated tremors by two weeks and die at 3–4 months due to sleep apnea. While it does not mimic the autoimmune demyelination of MS, this model facilitates an analysis of the remyelinating ability of transplant derived OLs. Recent advances in this field (Figure 1) came after the characterization of OPCs from the neonatal rat brain [7] and ligands that control OPC proliferation, differentiation and survival in vitro [8,9]. This allowed the amplification and transplant of pure OPCs populations [10], identification of the optimal maturation stage for myelination [11] and ultimately the rescue of the Shi motor phenotype and lethality [12,13,14]. The Shi mouse model is now a graft-curable genetic lethal disease, and Shi mice have been used to estimate the minimal number of wild-type cells necessary for functional rescue (7% graft chimerism) [13]. This may represent an upper limit, as co-transplants with adjunctive MSCs improves the survival of transplanted OPCs [15].

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