Stem cell biology and its therapeutic applications in the setting of spinal cord injury

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✓ The development of an acute traumatic spinal cord injury (SCI) inevitably leads to a complex cascade of ischemia and inflammation that results in significant scar tissue formation. The development of such scar tissue provides a severe impediment to neural regeneration and healing with restoration of function. A multimodal approach to treatment is required because SCIs occur with differing levels of severity and over different lengths of time. To achieve significant breakthroughs in outcomes, such approaches must combine both neuroprotective and neuroregenerative treatments. Novel techniques modulating endogenous stem cells demonstrate great promise in promoting neuroregeneration and restoring function.

Abbreviations used in this paper: bFGF = β-fibroblast growth factor; CNS = central nervous system; ESC = embryonic stem cell; FGF = fibroblast growth factor; NSC = neural stem cell; SCI = spinal cord injury; Shh = sonic hedgehog; SVZ = subventricular zone.

Abstract

✓ The development of an acute traumatic spinal cord injury (SCI) inevitably leads to a complex cascade of ischemia and inflammation that results in significant scar tissue formation. The development of such scar tissue provides a severe impediment to neural regeneration and healing with restoration of function. A multimodal approach to treatment is required because SCIs occur with differing levels of severity and over different lengths of time. To achieve significant breakthroughs in outcomes, such approaches must combine both neuroprotective and neuroregenerative treatments. Novel techniques modulating endogenous stem cells demonstrate great promise in promoting neuroregeneration and restoring function.

In the United States, the effects of SCI on society and healthcare are staggering. As many as 300,000 persons live with chronic disabilities related to SCI, and each year new SCIs affect 10,000–14,000 people (mean age at injury, 30 years).14 The annual cost to society is estimated to reach $8 billion, and the individual costs to patients can reach $1.35 million over their lifetime. As our ability to prolong the lives of these patients progresses, these costs would be expected to increase proportionally. Impressive strides have been made in the ability to provide disabled patients societal access. Nonetheless, the ultimate goal of medical science should be to restore neurological function corresponding to these patients' preinjured levels.

The severity of SCI ranges from complete paraplegia to incomplete myelopathy or paraparesis. Regardless of the degree of injury, the mechanism of injury is a crucial factor in determining a patient's treatment and likelihood of recovery. In contusive injuries significant compressive force is applied to the spinal cord. The initial trauma is related to destructive shearing and laceration of the nervous tissue. Progressive disruption of axonal transmission and subsequent neuronal and axonal degeneration yield to the formation of astrocytic scar tissue. In such cases, the treatment algorithm must include spinal realignment and stabilization, if necessary; prevention of ischemia and demyelination from the secondary injury cascade; and finally, the promotion of neural regeneration.

In contradistinction to low-impact or slowly progressive injuries (such as those caused by tumors), the first step in treatment must be decompression by removal of the offending lesion. Given the chronic ischemic state of injured tissue in this circumstance, adequate tissue perfusion must be maintained. In the longer term, regenerative therapies, including techniques to promote remyelination or prevent dysmyelination, can be considered.

In 1980 Richardson et al.27 published the first scientific evidence of the regenerative ability of the injured spinal cord. This finding led to a shift in thinking away from merely helping disabled patients integrate into society to developing research strategies aimed at restoring function. Although the results in animal models have been promising, models of treatment translatable to human patients are still lacking. One limiting factor may be the lack of recognition that SCI represents a complex injury cascade (Fig. 1). It therefore follows that no single “magic bullet” will address the requirements of a therapeutic modality that could lead to functional recovery. Instead, a multimodality approach is needed to make meaningful gains in clinical treatment. In general, multimodal paradigms can be divided into those that focus on ameliorating the secondary injury cascade (neuroprotection), and those that target re-myelination and axonal and neuronal regeneration (neuroregeneration). To date, most work on the potential benefits of stem cell therapy in treating SCI has concentrated on neuroregeneration, the focus of this article.

Fig. 1.
Fig. 1.

Outline of the primary and secondary injury cascades after acute traumatic SCI. Originally published in Horn EM, Forage J, Sonntag VKH: Acute treatment of patients with spinal cord injuries, in Herkowitz HN, Gorfin SR, Eismont FJ, et al (eds): Rothman-Simeone the Spine, ed 5. St. Louis: Elsevier, 2005. Copyright Barrow Neurological Institute.

Progenitor Cells Versus Stem Cells

When considering regenerative therapeutic options for the treatment of SCI, it is necessary to fully understand the basics of developmental cell biology. During development, pluripotent embryonic cells slowly lose their ability to transdifferentiate. Embryonic stem cells arise from the inner cell mass.31 Previously it was assumed that stem cells cease to be active in adult mammals. In fact, they are present in many different organ systems. Tissue restriction plays a role in limiting the possible fates of these cells more than in their embryonic counterparts. Even these cells may cross fate lines and generate other tissues, although whether this process represents cell–cell fusion or actual transdifferentiation is controversial. Ideally, there would be no difference between the fate of a population of adult stem cells in vitro or in vivo.11

With this understanding, stem cells demonstrate a multi-potent nature (Fig. 2), and their capacity for self-renewal is unlimited. They are concentrated in the hippocampus and SVZ of the CNS (Fig. 3). Similarly, progenitor cells have multiple potential destinies. However, they have far fewer potential fates than stem cells. Although the potential of progenitor cells for further differentiation is much greater than that of mature cells, their capacity for renewal is more limited than that of stem cells. This robustness and flexibility makes stem cells ideally suited for study in the treatment of SCI and concomitantly avoids the ethical dilemmas associated with embryonically derived progenitor cell lines.

Fig. 2.
Fig. 2.

Diagram demonstrating the pluripotent nature of ESCs. Pluripotent stem cells develop under the influence of various growth factors into multipotent progenitors that can then form either neuronal, oligodendroglial, or astrocytic cells. This process can be modified in vitro and subsequently result in cells that can be transplanted at the site of injury with the potential for therapeutic benefit. Originally published in Gantwerker BP, Hoffer A, Preul MC, Theodore N: Current concepts in nerve regeneration after traumatic brain injury. Barrow Quarterly 23:1–19, 2007. With permission from Barrow Neurological Institute.

Fig. 3.
Fig. 3.

The 2 niches containing NSCs in the CNS of adult mammals. Upper: Adult hippocampus. Lower: Longitudinal section of the adult mouse brain shows the SVZ and rostral migratory stream (RMS). Neuronal precursors migrate tangentially along the RMS from the SVZ to the olfactory bulb. Originally published in Dashti SR, Wilson J, Hu J, Selman WR, Spetzler RF, Nakaji P: Neural regenerative options in the management of ischemic brain injury. Barrow Quarterly 23:4–7, 2007. With permission from Barrow Neurological Institute.

Endogenous Stem Cells

Strategies for cellular replacement have involved both endogenous and exogenous sources of stem cells. Manipulation of endogenous stem cells offers an inherently attractive advantage: it avoids the need for further trauma caused by cellular transplantation while obviating the need for chronic immunosuppressive therapies. Furthermore, the ethical dilemmas posed by the need for ESCs are eliminated. Efforts to stimulate endogenous precursor cells to migrate to areas of injury have allowed the regions where these cells are found to be characterized. Rests of actively dividing stem cells are located in adult mammals, and these cells can be activated and remodeled in the event of an injury.15 The remodeling process continues after traumatic injury.7

Such remodeling primarily occurs in the area of injury nearest to the site of impact. Based on studies of staining with glial fibrillary acidic protein, an upregulation of reactive astrocytosis leads to the formation of scar tissue about 3 weeks after injury. Based on staining with neuronal nuclei (NeuN), adjacent gray matter neurons hypertrophy at the same time.29 The largest rests of NSCs are found in the SVZ and dentate gyrus of the hippocampus.24 Rests are also found in the ependymal lining of the spinal cord, where they actively divide in the presence of an injury.3,9,13,18

Neuroregeneration

After secondary injury, the potential for neuroregenerative therapies begins. However, the presence of the astrocytic scar is the major impediment to the restoration of functional electrochemical synapses and axonal recovery. If these limitations can be attenuated or overcome, it is hoped that restorative therapies may enable repair at the site of and downstream from the injury. Several strategies have been used to help achieve this goal in the injured spinal cord.

One strategy involves the use of activated macrophages, which are injected into the site of injury with the hope of reducing the concentration of postinjury inhibitory factors. Under normal circumstances, infiltration by macrophages into the site of injury peaks 5–7 days after injury.5,25 Although uncontrolled inflammation exacerbates neuronal loss after SCI, a controlled inflammatory response seems to ameliorate damaging effects.6 Theoretically, these macrophages aid in the autophagocytosis of cellular debris and damaged myelin that contribute to the strong inhibition of regeneration after injury. After the CNS is injured, these macrophages may also provide a stimulus for changes in molecules of the extracellular matrix to remove barriers to axonal regeneration.10

Activated macrophages coexpress markers associated with radial glial cells, which possess properties of NSCs and may contribute to neural repair and regeneration.32 This therapy has been used in patients with a complete SCI in a Phase I trial.17 In this study, monocytes were isolated from patients' blood and incubated ex vivo with autologous dermis. The resulting macrophages were then injected into the spinal cord of 8 patients within 14 days of a complete SCI. Of these patients, 3 recovered clinically significant neurological motor and sensory function (improving from American Spinal Injury Association Grade A to C). No adverse events were related to the injection of the macrophages. Phase II trials of this therapy are now underway worldwide.

Direct injection of stem cells in animal models dramatically improves functional recovery. Cellular transplantation has been used previously in these models, focusing on the ability of xenografts of pluripotent ESCs to incorporate into the cellular structure of the injured spinal cord and produce functional improvements in animal behavior.1,7,8,19,26,28,30,33 The mechanism underlying the improvement is controversial. It may be the result of transplanted ESCs maturing into myelinating oligodendrocytes, even though a sizable proportion of these cells develop along an astrocytic lineage.1,7,8,19,28,33 Furthermore, the transplantation of xenografted cells requires the coadministration of corticosteroids during the experimental period to prevent their rejection, which can confound the results.19,28 Work in humans has been limited.12 Compounding the difficulties of experimentation in humans is the ethical dilemma associated with the use of ESCs. Consequently, other solutions, including the use of stem cells derived from bone marrow and stimulation of endogenous stem cells, have been investigated.

The activation and promotion of endogenous stem cells are of particular interest because 500,000–2,000,000 new cells are produced at the site of the injury within a month.22 These endogenous cells are upregulated after a contusion injury to the spinal cord.16,20,21 Most of these cells originate near the ependyma of the central spinal canal (Fig. 4). The greatest level of cellular induction occurs 3–7 days after injury. In their unaltered state, these cells develop primarily along astrocytic lineages, thus contributing to scar formation and thereby inhibiting a restorative response. A key goal of current research efforts is modification of this normal inhibitory response. Specifically, the goal is to alter the cellular fate of these endogenous stem cells so that they develop into cell types that can aid in axonal preservation and repair.

Fig. 4.
Fig. 4.

Photomicrograph of bromodeoxyuridine-stained cells dividing around the central canal in the spinal cord of an adult rodent exposed to recombinant Shh after sustaining a demyelinating lesion. These cells represent endogenous neural progenitors stimulated by the combination of demyelination and Shh. Fluorescent stain for bromodeoxyuridine (original magnification × 200). Originally published in Bambakidis NC, Theodore N, Nakaji P, Harvey A, Sonntag VK, Preul MC, et al: Endogenous stem cell proliferation after central nervous system injury: alternative therapeutic options. Neurosurg Focus 19(3):E1, 2005. Used with permission from Neurosurgical Focus.

The process of endogenous stem cell differentiation in the injured adult nervous system has yet to be fully elucidated. Several agents, however, play important roles in modulating this process. Such agents have included analogs that stimulate the Shh pathway, and growth factors such as bFGF. The Shh protein, which is critical in oligodendroglial development and developmental neurogenesis, dramatically increases the number of neuronal progenitor cells in the spinal cord.3,4 A similar phenomenon is observed in rats with a contusion injury to the spinal cord. After oligodendrocytic precursors have been transplanted, markedly reduced demyelination and increased conduction velocity are observed across lesions. These findings correspond to significant preservation of behavioral function correlating to the reduction of cellular damage observed in treated animals (Figs. 5 and 6).2,3 The availability of small-molecule analogs to the Shh pathway that may be administered intravenously allows these experimental findings to be reproduced while obviating the need for direct injection into the injured spinal cord. In recent experiments involving contusive SCI, these agents upregulated endogenous cell populations; further work is ongoing.

Fig. 5.
Fig. 5.

A: Bar graph shows elevation in the cell counts of actively dividing cells in the spinal cord sections of adult rats. Rats with a spinal cord lesion were treated with a low dose (3.0 μl) or high dose (6.0 μl) of Shh. Rats without lesions were given a high dose of Shh. The number of proliferating cells significantly increased after rats with a lesion were exposed to Shh. Data were analyzed with repeated measures analysis of variance, followed by the Student– Newman– Keuls post hoc t-test (* p < 0.01). Originally published in Bambakidis NC, Theodore N, Nakaji P, Harvey A, Sonntag VK, Preul MC, et al: Endogenous stem cell proliferation after central nervous system injury: alternative therapeutic options. Neurosurg Focus 19(3):E1, 2005. Used with permission from Neurosurgical Focus.

Fig. 6.
Fig. 6.

Photomicrographs demonstrating diffuse positivity for nestin in dorsal regions of hyperproliferation from the spinal cords of rats treated with Shh after contusive SCI. Nestin is an intermediate filament protein found in CNS precursors. Left, original magnification ×100;C; center, original magnification × 50; and right, original magnification × 200. Characteristically, these primitive-appearing cells demonstrate bipolar morphological characteristics and are highly motile and proliferative. Originally published in Bambakidis NC, Theodore N, Nakaji P, Harvey A, Sonntag VK, Preul MC, et al: Endogenous stem cell proliferation after central nervous system injury: alternative therapeutic options. Neurosurg Focus 19(3):E1, 2005. Used with permission from Neurosurgical Focus.

Other studies have shown that bFGF expression is upregulated in rodents after traumatic injury. These bFGF-derived cells then differentiate into neuronal phenotypes.34 Additional agents that promote neuronal differentiation in genetically engineered mice after contusion include growth factors such as Mash1, epidermal growth factor, FGF2, and neurogenin2.23

Conclusions

A multimodal approach to the treatment of SCI is needed if significant breakthroughs in treatment and recovery are to be expected. Such treatment must be thought of as occurring temporally. During the acute period the best clinical treatment is required. During the subacute period neuroprotective treatment may be beneficial. Finally, during the delayed period neuroregenerative therapy is required (Fig. 7). As more investigations in the expanding field of stem cell biology are performed, particularly when applied to the stimulation and manipulation of endogenous stem cell populations, significant advances in the treatment of SCI may be expected.

Fig. 7.
Fig. 7.

Triphasic treatment paradigm for SCI. A: Illustration shows optimal clinical management during early minutes after spinal cord injury. Spinal protection during prehospital treatment, surgical stabilization, and spinal cord perfusion and oxygenation are key. B: The second step is neuroprotection from the administration of antiinflammatory agents such as minocycline, erythropoietin, riluzole, or 4-aminopyridine. C: In the weeks after injury, the last phase includes neuroregeneration based on promotion of endogenous stem cells, or other modalities to prevent scar formation, ameliorate axonal loss and demyelination, and restore function. Originally published in Horn EM, Preul MC, Sonntag VK, Bambakidis NC: Multimodality treatment of spinal cord injury: endogenous stem cells and other magic bullets. Barrow Quarterly 23:9–13, 2007. Used with permission from Barrow Neurological Institute.

References

  • 1

    Anderson DK: Transplants of fetal CNS grafts in chronic compression lesions of the adult cat spinal cord. Restor Neurol Neurosurg 2:3093251991

  • 2

    Bambakidis NCMiller RH: Transplantation of oligodendrocyte precursors and sonic hedgehog results in improved function and white matter sparing in the spinal cords of adult rats after contusion. Spine J 4:16262004

  • 3

    Bambakidis NCTheodore NNakaji PHarvey ASonntag VKPreul MC: Endogenous stem cell proliferation after central nervous system injury: alternative therapeutic options. Neurosurg Focus 19:3E12005

  • 4

    Bambakidis NCWang RZFranic LMiller RH: Sonic hedgehog-induced neural precursor proliferation after adult rodent spinal cord injury. J Neurosurg 99:1 Suppl70752003

  • 5

    Blight AR: Macrophages and inflammatory damage in spinal cord injury. J Neurotrauma 9:1 SupplS83S911992

  • 6

    Bomstein YMarder JBVitner KSmirnov ILisaey GButovsky O: Features of skin-coincubated macrophages that promote recovery from spinal cord injury. J Neuroimmunol 142:10162003

  • 7

    Cao QBenton RLWhittemore SR: Stem cell repair of central nervous system injury. J Neurosci Res 68:5015102002

  • 8

    Cao QLZhang YPHoward RMWalters WMTsoulfas PWhittemore SR: Pluripotent stem cells engrafted into the normal or lesioned adult rat spinal cord are restricted to a glial lineage. Exp Neurol 167:48582001

  • 9

    Clarke DFrisén J: Differentiation potential of adult stem cells. Curr Opin Genet Dev 11:5755802001

  • 10

    Fitch MTSilver J: Activated macrophages and the blood-brain barrier: inflammation after CNS injury leads to increases in putative inhibitory molecules. Exp Neurol 148:5876031997

  • 11

    Gantwerker BPHoffer APreul MCTheodore N: Current concepts in neural regeneration after traumatic brain injury. Barrow Quarterly 23:15192007

  • 12

    Garbossa DFontanella MFronda CBenevello CMuraca GDucati A: New strategies for repairing the injured spinal cord: the role of stem cells. Neurol Res 28:5005042006

  • 13

    Gritti ABonfanti LDoetsch FCaille IAlvarez-Buylla ALim DA: Multipotent neural stem cells reside into the rostral extension and olfactory bulb of adult rodents. J Neurosci 22:4374452002

  • 14

    Horn EMPreul MCSonntag VKBambakidis NC: Multimodality treatment of spinal cord injury: endogenous stem cells and other magic bullets. Barrow Quarterly 23:9142007

  • 15

    Horner PJGage FH: Regenerating the damaged central nervous system. Nature 407:9639702000

  • 16

    Ke YChi LXu RLuo CGozal DLiu R: Early response of endogenous adult neural progenitor cells to acute spinal cord injury in mice. Stem Cells 24:101110192006

  • 17

    Knoller NAuerbach GFulga VZelig GAttias JBakimer R: Clinical experience using incubated autologous macrophages as a treatment for complete spinal cord injury: phase I study results. J Neurosurg Spine 3:1731812005

  • 18

    Kruger GMMosher JTBixby SJoseph NIwashita TMorrison SJ: Neural crest stem cells persist in the adult gut but undergo changes in self-renewal, neuronal subtype potential, and factor responsiveness. Neuron 35:6576692002

  • 19

    McDonald JWLiu XZQu YLiu SMickey SKTuretsky D: Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord. Nat Med 5:141014121999

  • 20

    McTigue DMWei PStokes BT: Proliferation of NG2-positive cells and altered oligodendrocyte numbers in the contused rat spinal cord. J Neurosci 21:339234002001

  • 21

    Mothe AJTator CH: Proliferation, migration, and differentiation of endogenous ependymal region stem/progenitor cells following minimal spinal cord injury in the adult rat. Neuroscience 131:1771872005

  • 22

    Myckatyn TMMackinnon SEMcDonald JW: Stem cell transplantation and other novel techniques for promoting recovery from spinal cord injury. Transpl Immunol 12:3433582004

  • 23

    Ohori YYamamoto SNagao MSugimori MYamamoto NNakamura K: Growth factor treatment and genetic manipulation stimulate neurogenesis and oligodendrogenesis by endogenous neural progenitors in the injured adult spinal cord. J Neurosci 26:11948119602006

  • 24

    Palmer TDTakahashi JGage FH: The adult rat hippocampus contains primordial neural stem cells. Mol Cell Neurosci 8:3894041997

  • 25

    Popovich PGWei PStokes BT: Cellular inflammatory response after spinal cord injury in Sprague-Dawley and Lewis rats. J Comp Neurol 377:4434641997

  • 26

    Privat AMansour HRajaofetra NGeffard M: Intraspinal transplants of serotonergic neurons in the adult rat. Brain Res Bull 22:1231291989

  • 27

    Richardson PMMcGuinness UMAguayo AJ: Axons from CNS neurons regenerate into PNS grafts. Nature 284:2642651980

  • 28

    Rosenbluth JSchiff RLiang WLMenna GYoung W: Xenotransplantation of transgenic oligodendrocyte-lineage cells into spinal cord-injured adult rats. Exp Neurol 147:1721821997

  • 29

    Salman HGhosh PKernie SG: Subventricular zone neural stem cells remodel the brain following traumatic injury in adult mice. J Neurotrauma 21:2832922004

  • 30

    Stokes BTReier PJ: Fetal grafts alter chronic behavioral outcome after contusion damage to the adult rat spinal cord. Exp Neurol 116:1121992

  • 31

    Thomson JAItskovitz-Eldor JShapiro SSWaknitz MASwiergiel JJMarshall VS: Embryonic stem cell lines derived from human blastocysts. Science 282:114511471998

  • 32

    Wu DMiyamoto OShibuya SMori SNorimatsu HJanjua NA: Co-expression of radial glial marker in macrophages/ microglia in rat spinal cord contusion injury model. Brain Res 1051:1831882005

  • 33

    Wu SSuzuki YNoda TBai HKitada MKataoka K: Immunohistochemical and electron microscopic study of invasion and differentiation in spinal cord lesion of neural stem cells grafted through cerebrospinal fluid in rat. J Neurosci Res 69:9409452002

  • 34

    Xu YKitada MYamaguchi MDezawa MIde C: Increase in bFGF-responsive neural progenitor population following contusion injury of the adult rodent spinal cord. Neurosci Lett 397:1741792006

Article Information

Address correspondence to: Nicholas C. Bambakidis, M.D., c/o Neuroscience Publications, Barrow Neurological Institute, 350 West Thomas Road, Phoenix, Arizona 85013. email: neuropub@chw.edu.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Outline of the primary and secondary injury cascades after acute traumatic SCI. Originally published in Horn EM, Forage J, Sonntag VKH: Acute treatment of patients with spinal cord injuries, in Herkowitz HN, Gorfin SR, Eismont FJ, et al (eds): Rothman-Simeone the Spine, ed 5. St. Louis: Elsevier, 2005. Copyright Barrow Neurological Institute.

  • View in gallery

    Diagram demonstrating the pluripotent nature of ESCs. Pluripotent stem cells develop under the influence of various growth factors into multipotent progenitors that can then form either neuronal, oligodendroglial, or astrocytic cells. This process can be modified in vitro and subsequently result in cells that can be transplanted at the site of injury with the potential for therapeutic benefit. Originally published in Gantwerker BP, Hoffer A, Preul MC, Theodore N: Current concepts in nerve regeneration after traumatic brain injury. Barrow Quarterly 23:1–19, 2007. With permission from Barrow Neurological Institute.

  • View in gallery

    The 2 niches containing NSCs in the CNS of adult mammals. Upper: Adult hippocampus. Lower: Longitudinal section of the adult mouse brain shows the SVZ and rostral migratory stream (RMS). Neuronal precursors migrate tangentially along the RMS from the SVZ to the olfactory bulb. Originally published in Dashti SR, Wilson J, Hu J, Selman WR, Spetzler RF, Nakaji P: Neural regenerative options in the management of ischemic brain injury. Barrow Quarterly 23:4–7, 2007. With permission from Barrow Neurological Institute.

  • View in gallery

    Photomicrograph of bromodeoxyuridine-stained cells dividing around the central canal in the spinal cord of an adult rodent exposed to recombinant Shh after sustaining a demyelinating lesion. These cells represent endogenous neural progenitors stimulated by the combination of demyelination and Shh. Fluorescent stain for bromodeoxyuridine (original magnification × 200). Originally published in Bambakidis NC, Theodore N, Nakaji P, Harvey A, Sonntag VK, Preul MC, et al: Endogenous stem cell proliferation after central nervous system injury: alternative therapeutic options. Neurosurg Focus 19(3):E1, 2005. Used with permission from Neurosurgical Focus.

  • View in gallery

    A: Bar graph shows elevation in the cell counts of actively dividing cells in the spinal cord sections of adult rats. Rats with a spinal cord lesion were treated with a low dose (3.0 μl) or high dose (6.0 μl) of Shh. Rats without lesions were given a high dose of Shh. The number of proliferating cells significantly increased after rats with a lesion were exposed to Shh. Data were analyzed with repeated measures analysis of variance, followed by the Student– Newman– Keuls post hoc t-test (* p < 0.01). Originally published in Bambakidis NC, Theodore N, Nakaji P, Harvey A, Sonntag VK, Preul MC, et al: Endogenous stem cell proliferation after central nervous system injury: alternative therapeutic options. Neurosurg Focus 19(3):E1, 2005. Used with permission from Neurosurgical Focus.

  • View in gallery

    Photomicrographs demonstrating diffuse positivity for nestin in dorsal regions of hyperproliferation from the spinal cords of rats treated with Shh after contusive SCI. Nestin is an intermediate filament protein found in CNS precursors. Left, original magnification ×100;C; center, original magnification × 50; and right, original magnification × 200. Characteristically, these primitive-appearing cells demonstrate bipolar morphological characteristics and are highly motile and proliferative. Originally published in Bambakidis NC, Theodore N, Nakaji P, Harvey A, Sonntag VK, Preul MC, et al: Endogenous stem cell proliferation after central nervous system injury: alternative therapeutic options. Neurosurg Focus 19(3):E1, 2005. Used with permission from Neurosurgical Focus.

  • View in gallery

    Triphasic treatment paradigm for SCI. A: Illustration shows optimal clinical management during early minutes after spinal cord injury. Spinal protection during prehospital treatment, surgical stabilization, and spinal cord perfusion and oxygenation are key. B: The second step is neuroprotection from the administration of antiinflammatory agents such as minocycline, erythropoietin, riluzole, or 4-aminopyridine. C: In the weeks after injury, the last phase includes neuroregeneration based on promotion of endogenous stem cells, or other modalities to prevent scar formation, ameliorate axonal loss and demyelination, and restore function. Originally published in Horn EM, Preul MC, Sonntag VK, Bambakidis NC: Multimodality treatment of spinal cord injury: endogenous stem cells and other magic bullets. Barrow Quarterly 23:9–13, 2007. Used with permission from Barrow Neurological Institute.

References

1

Anderson DK: Transplants of fetal CNS grafts in chronic compression lesions of the adult cat spinal cord. Restor Neurol Neurosurg 2:3093251991

2

Bambakidis NCMiller RH: Transplantation of oligodendrocyte precursors and sonic hedgehog results in improved function and white matter sparing in the spinal cords of adult rats after contusion. Spine J 4:16262004

3

Bambakidis NCTheodore NNakaji PHarvey ASonntag VKPreul MC: Endogenous stem cell proliferation after central nervous system injury: alternative therapeutic options. Neurosurg Focus 19:3E12005

4

Bambakidis NCWang RZFranic LMiller RH: Sonic hedgehog-induced neural precursor proliferation after adult rodent spinal cord injury. J Neurosurg 99:1 Suppl70752003

5

Blight AR: Macrophages and inflammatory damage in spinal cord injury. J Neurotrauma 9:1 SupplS83S911992

6

Bomstein YMarder JBVitner KSmirnov ILisaey GButovsky O: Features of skin-coincubated macrophages that promote recovery from spinal cord injury. J Neuroimmunol 142:10162003

7

Cao QBenton RLWhittemore SR: Stem cell repair of central nervous system injury. J Neurosci Res 68:5015102002

8

Cao QLZhang YPHoward RMWalters WMTsoulfas PWhittemore SR: Pluripotent stem cells engrafted into the normal or lesioned adult rat spinal cord are restricted to a glial lineage. Exp Neurol 167:48582001

9

Clarke DFrisén J: Differentiation potential of adult stem cells. Curr Opin Genet Dev 11:5755802001

10

Fitch MTSilver J: Activated macrophages and the blood-brain barrier: inflammation after CNS injury leads to increases in putative inhibitory molecules. Exp Neurol 148:5876031997

11

Gantwerker BPHoffer APreul MCTheodore N: Current concepts in neural regeneration after traumatic brain injury. Barrow Quarterly 23:15192007

12

Garbossa DFontanella MFronda CBenevello CMuraca GDucati A: New strategies for repairing the injured spinal cord: the role of stem cells. Neurol Res 28:5005042006

13

Gritti ABonfanti LDoetsch FCaille IAlvarez-Buylla ALim DA: Multipotent neural stem cells reside into the rostral extension and olfactory bulb of adult rodents. J Neurosci 22:4374452002

14

Horn EMPreul MCSonntag VKBambakidis NC: Multimodality treatment of spinal cord injury: endogenous stem cells and other magic bullets. Barrow Quarterly 23:9142007

15

Horner PJGage FH: Regenerating the damaged central nervous system. Nature 407:9639702000

16

Ke YChi LXu RLuo CGozal DLiu R: Early response of endogenous adult neural progenitor cells to acute spinal cord injury in mice. Stem Cells 24:101110192006

17

Knoller NAuerbach GFulga VZelig GAttias JBakimer R: Clinical experience using incubated autologous macrophages as a treatment for complete spinal cord injury: phase I study results. J Neurosurg Spine 3:1731812005

18

Kruger GMMosher JTBixby SJoseph NIwashita TMorrison SJ: Neural crest stem cells persist in the adult gut but undergo changes in self-renewal, neuronal subtype potential, and factor responsiveness. Neuron 35:6576692002

19

McDonald JWLiu XZQu YLiu SMickey SKTuretsky D: Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord. Nat Med 5:141014121999

20

McTigue DMWei PStokes BT: Proliferation of NG2-positive cells and altered oligodendrocyte numbers in the contused rat spinal cord. J Neurosci 21:339234002001

21

Mothe AJTator CH: Proliferation, migration, and differentiation of endogenous ependymal region stem/progenitor cells following minimal spinal cord injury in the adult rat. Neuroscience 131:1771872005

22

Myckatyn TMMackinnon SEMcDonald JW: Stem cell transplantation and other novel techniques for promoting recovery from spinal cord injury. Transpl Immunol 12:3433582004

23

Ohori YYamamoto SNagao MSugimori MYamamoto NNakamura K: Growth factor treatment and genetic manipulation stimulate neurogenesis and oligodendrogenesis by endogenous neural progenitors in the injured adult spinal cord. J Neurosci 26:11948119602006

24

Palmer TDTakahashi JGage FH: The adult rat hippocampus contains primordial neural stem cells. Mol Cell Neurosci 8:3894041997

25

Popovich PGWei PStokes BT: Cellular inflammatory response after spinal cord injury in Sprague-Dawley and Lewis rats. J Comp Neurol 377:4434641997

26

Privat AMansour HRajaofetra NGeffard M: Intraspinal transplants of serotonergic neurons in the adult rat. Brain Res Bull 22:1231291989

27

Richardson PMMcGuinness UMAguayo AJ: Axons from CNS neurons regenerate into PNS grafts. Nature 284:2642651980

28

Rosenbluth JSchiff RLiang WLMenna GYoung W: Xenotransplantation of transgenic oligodendrocyte-lineage cells into spinal cord-injured adult rats. Exp Neurol 147:1721821997

29

Salman HGhosh PKernie SG: Subventricular zone neural stem cells remodel the brain following traumatic injury in adult mice. J Neurotrauma 21:2832922004

30

Stokes BTReier PJ: Fetal grafts alter chronic behavioral outcome after contusion damage to the adult rat spinal cord. Exp Neurol 116:1121992

31

Thomson JAItskovitz-Eldor JShapiro SSWaknitz MASwiergiel JJMarshall VS: Embryonic stem cell lines derived from human blastocysts. Science 282:114511471998

32

Wu DMiyamoto OShibuya SMori SNorimatsu HJanjua NA: Co-expression of radial glial marker in macrophages/ microglia in rat spinal cord contusion injury model. Brain Res 1051:1831882005

33

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