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Teruhisa Kazui
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Ann Thorac Surg 2006;81:2227-2234
© 2006 The Society of Thoracic Surgeons

Original article: Cardiovascular

Intrathecal Injection of Bone Marrow Stromal Cells Attenuates Neurologic Injury After Spinal Cord Ischemia

Enyi Shi, MD, PhD a , Teruhisa Kazui, MD, PhD a , * , Xiaojing Jiang, MD b , Naoki Washiyama, MD, PhD a , Katsushi Yamashita, MD, PhD a , Hitoshi Terada, MD, PhD a , Abul Hasan Muhammad Bashar, MBBS, PhD a

a First Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan
b Department of Anesthesiology, Hamamatsu University School of Medicine, Hamamatsu, Japan

Accepted for publication December 16, 2005.

* Address correspondence to Dr Kazui, First Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431-3192 Japan (Email: tkazui{at}hama-med.ac.jp).

Presented at the Forty-second Annual Meeting of The Society of Thoracic Surgeons, Chicago, IL, Jan 30–Feb 1, 2006.


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Discussion
 Acknowledgments
 References
 
BACKGROUND: It has been shown that transplantation of bone marrow stromal cells (MSCs) into the ischemic brain improves functional outcome. We sought to investigate whether intrathecal injection of MSCs can attenuate neurologic injury of spinal cord ischemia.

METHODS: Rabbit MSCs were expanded in vitro and were pre-labeled with bromodeoxyuridine. Spinal cord ischemia was induced in rabbits by infrarenal aortic occlusion. Group A and control A were subjected to a 20-minute ischemia and the ischemic duration was extended to 30 minutes in group B and control B. Two days before spinal cord ischemia, 1x108 MSCs were intrathecally injected into groups A and B, whereas vehicle alone was injected into the control groups. Hind-limb motor function was assessed during a 14-day recovery period with Tarlov criteria, and then histologic examination was performed.

RESULTS: Marrow stromal cells survived and engrafted into the spinal cord 2 days after transplantation, and more MSCs were found in the lumbar spinal cord (ischemic segment) than in the thoracic spinal cord (nonischemic segment) at 14 days. Compared with their respective control groups, Tarlov scores were significantly higher in both groups A and B (p < 0.05, group A vs control A, at 2, 7, and 14 days; p < 0.05, group B vs control B, at 1, 2, 7, and 14 days, respectively). The number of intact motor neurons was much higher in the two experimental groups (p < 0.01 vs the corresponding control groups, respectively).

CONCLUSIONS: Intrathecal injection of MSCs attenuates ischemic injury of spinal cord.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Discussion
 Acknowledgments
 References
 
Paraplegia, which is attributed primarily to temporary or permanent spinal cord ischemia, remains a major devastating and unpredictable complication after surgical repair of descending and thoracoabdominal aortic aneurysms [1, 2]. Regardless of the progress with surgical techniques and pharmacologic interventions, the complication still cannot be completely prevented [3].

Cell transplantation is presently believed to be an effective way to repair central nervous system injuries. Bone marrow cells are considered to be a source for cell transplantation therapy and are given more and more consideration [4, 5]. The precursors of nonhematopoietic tissues in bone marrow cells are referred to as mesenchymal stem cells or marrow stromal cells (MSCs). In different microenvironments, MSCs not only differentiate into multiple mesodermal lineage cells such as osteoblasts [6], chondrocytes [7], and adipocytes [8], but MSCs also adopt neuroectodermal cell fate [9, 10]. Recently it has been reported that MSCs are capable of developing into astrocytes, microglia, macroglia, and neurons both in vitro and in vivo [11–14]. Marrow stromal cells grown out of bone marrow cell suspensions can be efficiently expanded by their selective attachment to tissue culture plastic [15–17]. Transplantation of MSCs into the brain has demonstrated reduced functional deficits and lesion size associated with cerebral ischemia [9, 15, 18]. Improved functional recovery has also been reported after transplantation of MSCs into spinal cords suffering contusion and hemisection injury [19–22]. Collectively these results have led to the hypothesis that transplantation of MSCs can be beneficial in treating neurologic disorders of spinal cord ischemia. In contrast to the accumulating data about the benefits of transplantation of MSCs after central nervous system injuries, there is no work focused on the possible neuroprotective effects of transplantation of MSCs before the induction of injury. Considering the risk of additional neurologic damage caused by direct local injection, intrathecal injection of MSCs is regarded as a possible alternative way that would cause minimum damage to the spinal cord. Therefore the aims of this study were to determine whether MSCs injected intrathecally can survive and migrate into the spinal cord and whether transplantation of MSCs 2 days before the induction of ischemia can attenuate neurologic injuries of spinal cord ischemia in a well-characterized rabbit model.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Discussion
 Acknowledgments
 References
 
Animal Care and Surgical Procedure
Japanese white rabbits weighing 1.8 to 2.6 kg were used in the study. The animal protocol was approved by the Ethics Review Committee for Animal Experimentation of Hamamatsu University School of Medicine and was in accordance with the National Institutes of Health guide for the use and care of laboratory animals.

Surgical preparation was conducted according to the method described previously [23]. The rabbits were anesthetized with intravenous sodium pentobarbital (25 mg/kg) and were allowed to breathe spontaneously. Lidocaine (0.5%) was administered at the site of the skin incision as a local anesthesia. The left common carotid artery was cannulated with a 24-gauge catheter for monitoring the arterial pressure. Core body temperature was continuously monitored with a rectal probe and was maintained at about 38.5°C with the aid of a heating lamp. The infrarenal abdominal aorta was exposed through a transperitoneal approach. After systemic heparinization (200 U/kg), spinal cord ischemia was induced by crossclamping the abdominal aorta just distal to the renal arteries and just above the aortic bifurcation. At the end of the procedure, the clamps were released and the flank was closed in two layers.

Marrow Stromal Cells Culture
Bone marrow was harvested aseptically from tibias of rabbits approximately 2 months old. Nucleated cells were isolated by density gradient centrifugation using Percoll (1.073 g/mL) and were plated in growth medium consisting of DMEM/F12 supplemented with 20% fetal bovine serum and benzylpenicillin (1 x 105 U/mL) [24]. Marrow stromal cells were easily isolated in the medium by their tendency to adhere to plastic [15–17]. After 3 days the flasks were washed twice with phosphate buffered saline to remove nonadherent cells. The remaining cells were fed every third day. Cultures of MSCs were maintained at 50% confluence and were passaged 3 to 5 times. Bromodeoxyuridine (BrdU) (3 µg/mL) (Sigma, Louis, MO) was added into the medium 72 hours before transplantation [15]. Marrow stromal cells were harvested by trypsinization and were resuspended in DMEM for injection.

Intrathecal Injection
After anesthesia with pentobarbital, the intervertebral space between L5 and L6 was punctured with a 16-gauge needle and polyethylene-10 tubing was inserted through it into the subarachnoid space. The desired position of the catheter was confirmed by cautious aspiration of cerebrospinal fluid. After intrathecal injection of either the MSCs or the vehicle, the catheter was removed. Then, the animals were placed head up for 60 minutes. The animals were included in the study only if they had a normal hind-limb motor function 2 days after intrathecal injection.

Experimental Protocol
Rabbits were assigned to four groups, as shown in Figure 1. Group A (n = 10) and control A (n = 9) were subjected to a 20-minute ischemia, and the ischemic duration was extended to 30 minutes in group B (n = 8) and control B (n = 7). Two days before spinal cord ischemia, approximately 1 x 108 MSCs in a total fluid volume of 0.2 mL were intrathecally injected into each rabbit of groups A and B, whereas vehicle alone of the same volume was injected into the two corresponding control groups.


Figure 1
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  		Fig 1. Experimental groups and protocol. (MSCs = marrow stromal cells.)

 
Rabbits (n = 3) in a separate subset that received MSCs without undergoing aortic occlusion were sacrificed 2 days after the transplantation procedure.

Neurologic Assessment
On days 1, 2, 7, and 14 after ischemia, hind-limb motor function was assessed by blinded observers, using the modified Tarlov scale [25]: 0, no movement; 1, slight movement; 2, sit with assistance; 3, sit alone; 4, weak hop; and 5, normal hop.

Histologic Study
All animals of the four groups were sacrificed by a lethal injection of pentobarbital (200 mg/kg) 14 days after the operation, and the spinal cords were quickly removed. To identify cells derived from MSCs, frozen sections were treated with the FITC-labeled mouse monoclonal antibody against BrdU (Progen Biotechnik, Heidelberg, Deutschland) and were examined under fluorescence microscope. Bromodeoxyuridine-positive cells in the ventral gray matter (anterior to a line drawn through the central canal perpendicular to the vertical axis) of the lumbar (ischemic region) and thoracic (nonischemic region) spinal cords were counted and averaged in three slides. Paraffin embedded sections (4 µm) of lumbar spinal cords (L4 to L6) were stained with hematoxylin and eosin. Cases in which the cytoplasm was diffusely eosinophilic, the large motor neuron cells were considered to be necrotic or dead. When the cells demonstrated basophilic stippling (containing Nissl substance), the motor-neuron cells were considered to be viable or alive [26]. An investigator (who was unaware of the animal groups and neurologic outcomes) examined each slide. The intact motor neurons were counted in the ventral gray matter in three sections for each rabbit, and the numbers were then averaged.

Statistical Analysis
Statistical analysis of the neurologic score and the number of BrdU-positive cells and intact large motor neurons were performed with Mann-Whitney U tests. Statistical significance was defined as a p value of less than 0.05.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Discussion
 Acknowledgments
 References
 
Migration of Transplanted MSCs
Immunofluorescent-FITC (green) revealed BrdU-labeled MSCs. More than 90% of the cultured cells showed BrdU reactivity in vitro. Two days after injection, BrdU-labeled cells were found to be located on the surface of the spinal cord as well as into the white matter relatively close to the surface (Figs 2A, 2B). Similar distributions of BrdU-labeled cells were found in the thoracic spinal cords (nonischemic region) and lumbar spinal cords (ischemic region). Marrow stromal cells in the lumbar spinal cords survived the ischemic assault, and there was a tendency that the BrdU-labeled cells distributed more broadly in the lumbar spinal cords than in the thoracic segments 14 days after ischemia (Figs 2C–2F). Compared with the thoracic spinal cords, the BrdU-labeled cells migrated in a considerably great number into the ventral gray matter of the lumbar spinal cords (Table 1).


Figure 2
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  		Fig 2. Lumbar spinal cord 2 days after transplantation of marrow stromal cells (MSCs) without ischemia (original magnification, x100). (A) Fluorescence micrograph. (B) The corresponding hematoxylin and eosin staining section. Fluorescence micrographs of the spinal cord 14 days after transient ischemia (original magnification, x200). (C) White matter of the lumbar cord. (D) Gray matter of the lumbar cord. (E) White matter of the thoracic cord. (F) Gray matter of the thoracic cord. Immunofluorescent-FITC (green) shows bromodeoxyuridine-labeled MSCs. Many more MSCs were found in the gray matter of the ischemic spinal cord (lumbar) than in the nonischemic region (thoracic).

 

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  		Table 1. Number of Bromedeoxyuridine-Positive Cells in the Ventral Gray Matter of Thoracic (Nonischemic Region) and Lumbar (Ischemic Region) Spinal Cords
 
Neurologic Assessment
All rabbits showed normal hind-limb motor function 2 days after intrathecal injection prior to the induction of ischemia. The individual neurologic scores of the four groups at 1, 2, 7, and 14 days after reperfusion are shown in Figure 3. A 20-minute period of infrarenal aortic occlusion resulted in severe lower-extremity neurologic deficits in the controls, and previous transplantation of MSCs remarkably enhanced the recovery of motor function (group A vs control A; p < 0.01, at 2, 7, and 14 days, respectively). When the ischemia time was extended to 30 minutes, more severe lower-extremity neurologic deficits were induced, whereas significantly better neurologic function was still found in rabbits receiving MSCs transplantation (group B vs control B; p < 0.01 at 1 and 2 days, and p < 0.05 at 7 and 14 days, respectively).


Figure 3
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  		Fig 3. Neurologic function assessed at 1, 2, 7, and 14 days after ischemia. Triangles and circles represent individual rabbits.

 
Histologic Assessment
Four rabbits that underwent a sham operation were also enrolled in the histologic study. Representative photographs of sections stained with hematoxylin and eosin are shown in Figure 4. The results of counting viable motor neurons are summarized in Figure 5. In the sham-operated animals, the spinal cord was intact and many large motor neurons were present in the anterior horn (Fig 4A). A 20-minute ischemia induced severe neuronal damage in the control animals (control A) 14 days after the operation, as evidenced by vacuolization and frank necrosis (Fig 4B). More severe histologic damages were found in the control rabbits subjected to a 30-minute ischemia (control B) in which there was almost a total loss of the motor neurons (Fig 4D). In contrast, only slight changes were found in the lumbar spinal cords of both groups A and B (Figs 4C, 4D), and most of the motor neurons remained intact (p < 0.05 vs the corresponding control groups for both groups A and B).


Figure 4
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  		Fig 4. Representative sections of lumbar spinal cords stained with hematoxylin and eosin (original magnification, x100). (A) Sham-operated animal. (B) Control A. (C) Group A. (D) Control B. (E) Group B. Severe histologic damage was found in the control A and control B groups, whereas viable large motor neurons were preserved to a much greater extent in groups A and B.

 

Figure 5
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  		Fig 5. Number of large motor neurons in the ventral gray matter.

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Discussion
 Acknowledgments
 References
 
The data from the current study demonstrate that MSCs survive and migrate into the spinal cord after intrathecal injection and are more likely to enter the ischemic region than the nonischemic region. Another salient finding is that transplantation of MSCs 2 days previously significantly attenuates neurologic deficits caused by spinal cord ischemia.

Transplantation of MSCs has been performed by direct local injection into the cerebrum and spinal cord [5, 15, 20, 27, 28]. Although local injection delivers cells directly into acutely injured lesion, this invasive technique may cause additional damage to the spinal cord. In the present study, MSCs survived, spread to the pia mater and engrafted into the spinal cord within 2 days after intrathecal injection without neurologic injuries, suggesting that intrathecal injection can be performed as a promising way with minimum damage to transplant MSCs into the spinal cord. Marrow stromal cells injected into the fourth ventricle have been shown to be distributed through cerebrospinal fluid, and some of them were attached to the surface of the spinal cord and invaded into the cord lesion within 2 days [21]. Marrow stromal cells have also been delivered to the brain tissue through an intravenous route [9, 29]. Compared with the systemic administration, intrathecal injection allows more efficient delivery of cells into the spinal cord [30], and the possible side effects due to the migration of MSCs into tissues other than the spinal cord will be avoided.

Marrow stromal cells injected intravenously are more likely to migrate into the damaged brain than into the intact brain [18, 29, 31]. Bone marrow derived myogenic progenitors have been shown to selectively migrate into degenerating muscle [32]. We also found that more MSCs migrated into the gray matter in the ischemic region 14 days after ischemia, indicating that ischemia improves the migration of MSCs. The mechanisms responsible for grafted MSCs migration are not very clear. The upregulation of adhesion molecules in the ischemia-damaged area may be contributive, such as neural cell adhesion molecule, intercellular adhesion molecule, and vascular cell adhesion molecule [33]. Correspondingly, several adhesion-related antigens have been found to be expressed on MSCs [15]. It may also facilitate cell migration that MSCs produce and functionally adhere to extracellular matrix molecules [34, 35].

In most studies, if not all, investigations were focused on the capacity of MSCs to facilitate functional recovery after injuries of the central nervous system. In the present study, functional deficits caused by spinal cord ischemia were markedly ameliorated by prophylactic transplantation of MSCs. The protective effects of MSCs may be derived from the production of trophic factors and cytokines, rather than the replacement or integration of MSCs into the spinal cord. Although MSCs have been found to survive and express neuronal phenotypic proteins after transplantation into the brain, the engrafted MSCs did not contribute to reestablish normal tissue cytoarchitecture after cerebral ischemia. No clear evidence showed that MSCs differentiated into neurons and developed contacts with other neurons [15]. The functional improvement after cerebral ischemia by transplantation of MSCs was not dependent on the establishment of new neural circuits between grafts and host or was not dependent on the reduction of infarct size [36]. Interaction of transplanted MSCs with the host tissue may lead to the production of growth factors, which may contribute to protect neurons against ischemia and improve motor function. Levels of insulin-like growth factor-1 and its receptor can be markedly increased in the ischemic brain tissue treated with MSCs [37]. Insulin-like growth factor-1 has been shown to prevent neuronal cell death and paraplegia resulting from spinal cord ischemia [38]. Transplantation of MSCs also upregulates the levels of endogenous vascular endothelial growth factor and vascular endothelial growth factor receptor 2 and enhances the angiogenesis in the host brain [18]. In experimental spinal cord injury, vascular endothelial growth factor improves functional outcome and decreases secondary degeneration [39]. In Zhao and colleagues' [36] study, MSCs continue to express collagen I and fibronectin 6 weeks after grafting. Both collagen I and fibronectin may participate in MSCs survival and differentiation, and may also be involved in the functional restoration of ischemic brain by activating integrin signal transduction. In addition, MSCs by themselves secrete cytokines and trophic factors, such as colony-stimulating factor-1, nerve growth factor, and brain-derived neurotrophic factor, which may promote the survival and differentiation of the neuronal tissue [40]. Cerebrospinal fluid from rats receiving MSCs 2 days previously enhanced the attachment and differentiation of neurosphere cells in vitro [21], which also suggests that some trophic substances might be released from MSCs into cerebrospinal fluid. Thus, some cytokines and trophic factors derived from the transplantation of MSCs may contribute to the neuroprotective effects observed in the current study. These cytokines and trophic factors may also be beneficial for MSCs themselves to survive ischemia.

Compared with embryonic stem cells and neural stem cells, MSCs can be readily harvested and expanded ex vivo. Moreover, autologous transplantation of MSCs would circumvent potential ethical and immune rejection considerations. We believe that this is the first time that prophylactic transplantation of MSCs has been shown to attenuate neurologic injury after spinal cord ischemia, which provides novel insights into the protective effects of MSCs against neurologic injury. Moreover, lumbar puncture can be readily performed without severe invasion. Thus we believe that prophylactic intrathecal injection of MSCs possesses a potential clinical value in the prevention of neurologic injury after thoracic aneurysm surgery.


   Discussion
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Discussion
Acknowledgments
 References
 
DR JOHN J. ELEFTERIADES (New Haven, CT): This is a fascinating study. I have one question for you. I can understand how the cells are swimming in the spinal fluid after you inject them, but I am still a little troubled: how do the cells actually migrate through the spinal cord into the deep tissues? Also, what evidence do you have that they really did migrate into the tissue itself?

DR SHI: Sorry, could you ask your question again?

DR ELEFTERIADES: We can understand how the injected cells are swimming in the fluid around the spinal cord, but how do they actually go through, how do they migrate into the tissue, and what proof do you have that they actually migrated?

DR SHI: The BrdU-labled cells could be detected in the spinal cord 2 days after injection, which was the proof that MSCs migrated into the tissue. When the stem cells are intrathecally injected into the subarachnoid space, they will first adhere to the surface of the spinal cord, and then the interaction between the host tissue and the transplanted cells will induce the production of some adhesion molecules. These molecules may help the transplanted cells to migrate into the host tissue, I think. Of course, this is just a hypothesis.

DR GRAYSON H. WHEATLEY III (Phoenix, AZ): I wanted to turn the tables a little bit. Have you performed intrathecal injections of bone marrow cells after inducing ischemia? You have carefully demonstrated that you can prophylactically inject these cells before an ischemic event, but did you inject these cells after the ischemia and see if you were able to get some similar type of results in some of the animals in the lab?

DR SHI: The purpose of our study was to see if prophylactic transplantation of cells has neuroprotective effects. The spinal cord ischemia studied in our experiment is different from other organ ischemia because it is a complication of surgery. We can know the accurate time when it occurs. So I think prevention of neurologic injury is more important than treatment of neurologic injury in this model. And in the previous study we also tried in some animals giving the cells two days after ischemia, but we didn't see better results about the recovery of motor function.

DR JOHN S. IKONOMIDIS (Charleston, SC): Did you test different cell concentrations to see if there is a relationship between cell concentration injected and recovery of function?

DR SHI: No, only this one concentration.

DR IKONOMIDIS: And how did you decide on the cell concentration that you used? Why did you decide to use that cell concentration?

DR SHI: The cell concentration was selected according to the references in the pilot experiment. Fortunately, we got a good result, which help us to make a decision that it is the final concentration in the current study.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Discussion
 Acknowledgments
References
 
Dr Shi is supported by the Japan Society for the Promotion of Science.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Discussion
 Acknowledgments
 References
 

  1. Svensson LG, Crawford ES, Hess KR, Coselli JS, Safi HJ. Experience with 1509 patients undergoing thoracoabdominal aortic operations J Vasc Surg 1993;17:357-370.[Medline]
  2. Coselli JS, LeMaire SA, Miller 3rd CC, et al. Mortality and paraplegia after thoracoabdominal aortic aneurysm repaira risk factor analysis. Ann Thorac Surg 2000;69:409-414.[Abstract/Free Full Text]
  3. Gharagozloo F, Larson J, Dausmann MJ, Neville Jr RF, Gomes MN. Spinal cord protection during surgical procedures on the descending thoracic and thoracoabdominal aortareview of current techniques. Chest 1996;109:799-809.[Medline]
  4. Eglitis MA, Dawson D, Park KW, Mouradian MM. Targeting of marrow-derived astrocytes to the ischemic brain Neuroreport 1999;10:1289-1292.[Medline]
  5. Chen J, Li Y, Chopp M. Intracerebral transplantation of bone marrow with BDNF after MCAo in rat Neuropharmacology 2000;39:711-716.[Medline]
  6. Dennis JE, Haynesworth SE, Young RG, Caplan AI. Osteogenesis in marrow-derived mesenchymal cell porous ceramic composites transplanted subcutaneouslyeffect of fibronectin and laminin on cell retention and rate of osteogenic expression. Cell Transplant 1992;1:23-32.[Medline]
  7. Lennon DP, Haynesworth SE, Young RG, Dennis JE, Caplan AI. A chemically defined medium supports in vitro proliferation and maintains the osteochondral potential of rat marrow-derived mesenchymal stem cells Exp Cell Res 1995;219:211-222.[Medline]
  8. Beresford JN, Bennett JH, Devlin C, Leboy PS, Owen ME. Evidence for an inverse relationship between the differentiation of adipocytic and osteogenic cells in rat marrow stromal cell cultures J Cell Sci 1992;102:341-351.[Abstract/Free Full Text]
  9. Honma T, Honmou O, Iihoshi S, et al. Intravenous infusion of immortalized human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat Exp Neurol 2005Epub ahead of print.
  10. Mezey E, Chandross KJ, Harta G, Maki RA, McKercher SR. Turning blood into braincells bearing neuronal antigens generated in vivo from bone marrow. Science 2000;290:1779-1782.[Abstract/Free Full Text]
  11. Eglitis MA, Mezey E. Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice Proc Natl Acad Sci U S A 1997;94:4080-4085.[Abstract/Free Full Text]
  12. Eglitis MA, Dawson D, Park KW, Mouradian MM. Targeting of marrow-derived astrocytes to the ischemic brain Neuroreport 1999;10:1289-1292.[Medline]
  13. Woodbury D, Schwarz EJ, Prockop DJ, Black IB. Adult rat and human bone marrow stromal cells differentiate into neurons J Neurosci Res 2000;61:364-370.[Medline]
  14. Mezey E, Key S, Vogelsang G, Szalayova I, Lange GD, Crain B. Transplanted bone marrow generates new neurons in human brains Proc Natl Acad Sci U S A 2003;100:1364-1369.[Abstract/Free Full Text]
  15. Chen J, Li Y, Wang L, Lu M, Zhang X, Chopp M. Therapeutic benefit of intracerebral transplantation of bone marrow stromal cells after cerebral ischemia in rats J Neurol Sci 2001;189:49-57.[Medline]
  16. Azizi SA, Stokes D, Augelli BJ, DiGirolamo C, Prockop DJ. Engraftment and migration of human bone marrow stromal cells implanted in the brains of albino rats—similarities to astrocyte grafts Proc Natl Acad Sci U S A 1998;95:3908-3913.[Abstract/Free Full Text]
  17. Colter DC, Class R, DiGirolamo CM, Prockop DJ. Rapid expansion of recycling stem cells in cultures of plastic-adherent cells from human bone marrow Proc Natl Acad Sci U S A 2000;97:3213-3218.[Abstract/Free Full Text]
  18. Chen J, Zhang ZG, Li Y, et al. Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats Circ Res 2003;92:692-699.[Abstract/Free Full Text]
  19. Chopp M, Zhang XH, Li Y, et al. Spinal cord injury in rattreatment with bone marrow stromal cell transplantation. Neuroreport 2000;11:3001-3005.[Medline]
  20. Hofstetter CP, Schwarz EJ, Hess D, et al. Marrow stromal cells form guiding strands in the injured spinal cord and promote recovery Proc Natl Acad Sci U S A 2002;99:2199-2204.[Abstract/Free Full Text]
  21. Ohta M, Suzuki Y, Noda T, et al. Bone marrow stromal cells infused into the cerebrospinal fluid promote functional recovery of the injured rat spinal cord with reduced cavity formation Exp Neurol 2004;187:266-278.[Medline]
  22. Neuhuber B, Timothy Himes B, Shumsky JS, Gallo G, Fischer I. Anon growth and recovery of function supported by human bone marrow stromal cells in the injured spinal cord exhibit donor variations Brain Res 2005;1035:73-85.[Medline]
  23. Shi E, Kazui T, Jiang X, et al. NS-7, a novel Na+/Ca2+ channel blocker, prevents neurologic injury after spinal cord ischemia in rabbits J Thorac Cardiovasc Surg 2005;129:364-371.[Abstract/Free Full Text]
  24. Thompson RB, Emani SM, Davis BH, et al. Comparison of intracardiac cell transplantationautologous skeletal myoblasts versus bone marrow cells. Circulation 2003;108:II264-II271.[Medline]
  25. Tarlov IM. Acute spinal cord compression paralysis J Neurosurg 1972;36:10-20.[Medline]
  26. Mutch WA, Graham MR, Halliday WC, Thiessen DB, Girling LG. Use of neuroanesthesia adjuncts (hyperventilation and mannitol administration) improves neurological outcome after thoracic aortic cross-clamping in dogs Stroke 1993;24:1204-1210.[Abstract/Free Full Text]
  27. Ankeny DP, McTigue DM, Jakeman LB. Bone marrow transplants provide tissue protection and directional guidance for axons after contusive spinal cord injury in rats Exp Neurol 2004;190:17-31.[Medline]
  28. Zurita M, Vaquero J. Functional recovery in chronic paraplegia after bone marrow stromal cells transplantation Neuroreport 2004;15:1105-1108.[Medline]
  29. Chen J, Li y, Wang L. Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats Stroke 2001;32:1005-1011.[Abstract/Free Full Text]
  30. Bakshi A, Hunter C, Swanger S, Lepore A, Fischer I. Minimally invasive delivery of stem cells for spinal cord injuryadvantages of the lumbar puncture technique. J Neurosurg Spine 2004;1:330-337.[Medline]
  31. Lu D, Mahmood A, Wang L, Li Y, Lu M, Chopp M. Adult bone marrow stromal cells administered intravenously to rats after traumatic brain injury migrate into brain and improve neurological outcome Neuroreport 2001;12:559-563.[Medline]
  32. Ferrari G, Cusella-De Angelis G, Coletta M. Muscle regeneration by bone marrow-derived myogenic progenitors Science 1998;279:1528-1530.[Abstract/Free Full Text]
  33. Bonfanti L, Theodosis DT. Expression of polysialylated neural cell adhesion molecule by proliferating cells in the subependymal layer of the adult rat, in its rostral extension and in the olfactory bulb Neuroscience 1994;62:291-305.[Medline]
  34. Quesenberry PJ, Becker PS. Stem cell homingrolling, crawling, and nesting. Proc Natl Acad Sci U S A 1998;95:15155-15157.[Free Full Text]
  35. Kennedy DW, Abkowitz JL. Kinetics of central nervous system microglial and macrophage engraftmentanalysis using a transgenic bone marrow transplantation model. Blood 1997;90:986-993.[Abstract/Free Full Text]
  36. Zhao LR, Duan WM, Reyes M, Keene CD, Verfaillie CM, Low WC. Human bone marrow stem cells exhibit neural phenotypes and ameliorate neurological deficits after grafting into the ischemic brain of rats Exp Neurol 2002;174:11-20.[Medline]
  37. Zhang J, Li Y, Chen J, et al. Expression of insulin-like growth factor 1 and receptor in ischemic rats treated with human marrow stromal cells Brain Res 2004;1030:19-27.[Medline]
  38. Nakao Y, Otani H, Yamamura T, Hattori R, Osako M, Imamura H. Insulin-like growth factor 1 prevents neuronal cell death and paraplegia in the rabbit model of spinal cord ischemia J Thorac Cardiovasc Surg 2001;122:136-143.[Abstract/Free Full Text]
  39. Widenfalk J, Lipson A, Jubran M, et al. Vascular endothelial growth factor improves functional outcome and decreases secondary degeneration in experimental spinal cord contusion injury Neuroscience 2003;120:951-960.[Medline]
  40. Chen X, Katakowski M, Li Y, et al. Human bone marrow stromal cell cultures conditioned by traumatic brain tissue extractsgrowth factor production. J Neurosci Res 2002;69:687-691.[Medline]



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 J. Thorac. Cardiovasc. Surg.Home page
E. Shi, X. Jiang, T. Kazui, N. Washiyama, K. Yamashita, H. Terada, and A. H. M. Bashar
Nonviral gene transfer of hepatocyte growth factor attenuates neurologic injury after spinal cord ischemia in rabbits
J. Thorac. Cardiovasc. Surg., October 1, 2006; 132(4): 941 - 947.
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Abul Hasan Muhammad Bashar
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