Effects of intravenous administration of human bone marrow stromal cells after intracerebral hemorrhage in rats

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Object

The goal of this study was to investigate whether human bone marrow stromal cells (hBMSCs) administered by intravenous injection have a beneficial effect on outcome after intracerebral hemorrhage (ICH) in rats.

Methods

An ICH was induced in 54 adult male Wistar rats by a stereotactically guided injection of autologous blood into the right striatum. Intravenous infusion of the hBMSCs (3, 5, or 8 million cells) was performed 1 day after ICH, and for each dose group there was a control group that received injections of vehicle. Neurological function, which was evaluated using the Neurological Severity Score (NSS) and the corner turn test, was tested before and at 1, 7, and 14 days after ICH. After 14 days of survival, the area of encephalomalacia was calculated and histochemical labeling was performed.

For all three groups, there were no statistical differences in either the NSS or corner turn tests after 1 day. After 7 and 14 days, however, the three groups that received the hBMSCs showed significant improvement in functional scores compared with the control group. In addition, after 14 days there was significantly more striatal tissue loss in the placebo groups compared with each of the three treatment groups. The region of injury in the treated animals demonstrated a significantly increased presence of hBMSCs, immature neurons, neuronal migration, synaptogenesis, and newly formed DNA.

Conclusions

Intravenous administration of hBMSCs significantly improves neurological function in rats subjected to ICH. This improvement in the treated animals is associated with reduced tissue loss and increased local presence of the hBMSCs, mitotic activity, immature neurons, synaptogenesis, and neuronal migration.

Abbreviations used in this paper: BrdU = bromodeoxyuridine; DCX = doublecortin; hBMSC = human bone marrow stromal cell; ICH = intracerebral hemorrhage; mAb = monoclonal antibody; NSS = Neurological Severity Score; PBS = phosphate-buffered saline; SVZ = subventricular zone; TUJ1 = mAb Class III beta-tubulin isotype.

Article Information

Address reprint requests to: Donald Seyfried, M.D., Department of Neurosurgery, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, Michigan 48202. email: nsdos@neuro.hfh.edu.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    Bar graphs showing results of neurological functional assessment according to the NSS (left) and the corner turn test (right) for control and treatment groups of rats (injection of vehicle or 3, 5, or 8 million hBMSCs) 1 day before and 7 and 14 days after ICH. Abbreviations: D = day; n = number of rats; SEM = standard error of the mean.

  • View in gallery

    Bar graph showing area of tissue loss in the region of the ICH, expressed as a percentage of the normal hemisphere for control and treatment groups of rats (injection of vehicle or 3, 5, or 8 million hBMSCs).

  • View in gallery

    Photomicrographs and bar graphs showing values for DCX, mAb (MAB) 1281, BrdU, synaptophysin, and TUJ1 immunohistochemical labeling data for the three treatment (injection of 3, 5, and 8 million hBMSCs [hMSCs]) and control groups of rats. Arrows indicate cells or regions with positive staining. Original magnifications × 100 (panel with BrdU staining) and × 200 (all other panels).

  • View in gallery

    Photomicrograph showing BrdU colocalizing with TUJ1 in a subpopulation of cells near the injury zone. Arrow indicates cells with positive staining. Original magnification × 40.

References

1

Ashton BAAllen TDHowlett CREagleson CCHattori AOwen M: Formation of bone and cartilage by marrow stromal cells in diffusion chambers in vivo. Clin Orthop Relat Res 151:2943071980

2

Bennett JHJoyner CJTriffitt JTOwen ME: Adipocytic cells cultured from marrow have osteogenic potential. J Cell Sci 99:1311391991

3

Chen JLi YWang LZhang ZLu DLu M: Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke 32:100510112001

4

Chen JSanberg PRLi YWang LLu MWilling AE: Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats. Stroke 32:268226882001

5

Chen JZhang ZGLi YWang YWang LJiang H: Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke. Ann Neurol 53:7437512003

6

Chopp MZhang XHLi YWang LChen JLu D: Spinal cord injury in rat: treatment with bone marrow stromal cell transplantation. Neuroreport 11:300130052000

7

Eglitis MADawson DPark KWMouradian MM: Targeting of marrow-derived astrocytes to the ischemic brain. Neuroreport 10:128912921999

8

Feng YWalsh CA: Protein-protein interactions, cytoskeletal regulation and neuronal migration. Nat Rev Neurosci 2:4084162001

9

Fernandes HMGregson BSiddique SMendelow AD: Surgery in intracerebral hemorrhage: the uncertainty continues. Stroke 31:251125162000

10

Gong CBoulis NQian JTurner DEHoff JTKeep RF: Intracerebral hemorrhage-induced neuronal death. Neurosurgery 48:8758832001

11

Gong CHoff JTKeep RF: Acute inflammatory reaction following experimental intracerebral hemorrhage in rat. Brain Res 871:57652000

12

Hua YXi GKeep RFWu JJiang YHoff JT: Plasminogen activator inhibitor-l induction after experimental intracerebral hemorrhage. J Cereb Blood Flow Metab 22:55612002

13

Jeong SWChu KJung KHKim SUKim MRoh JK: Human neural stem cell transplantation promotes functional recovery in rats with experimental intracerebral hemorrhage. Stroke 34:225822632003

14

Kopen GCProckop DJPhinney DG: Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc Natl Acad Sci U S A 96:10711107161999

15

Li YChen JChen XGWang LGautam SCXu YX: Human marrow stromal cell therapy for stroke in rat: neurotrophins and functional recovery. Neurology 59:5145232002

16

Li YChen JWang LLu MChopp M: Treatment of stroke in rat with intracarotid administration of marrow stromal cells. Neurology 56:166616722001

17

Li YChopp MChen JWang LGautam SCXu YX: Intrastriatal transplantation of bone marrow nonhematopoietic cells improves functional recovery after stroke in adult mice. J Cereb Blood Flow Metab 20:131113192000

18

Lu DGoussev AChen JPannu PLi YMahmood A: Atorvastatin reduces neurological deficit and increases synaptogenesis, angiogenesis, and neuronal survival in rats subjected to traumatic brain injury. J Neurotrauma 21:21322004

19

Mahmood ALu DLu MChopp M: Treatment of traumatic brain injury in adult rats with intravenous administration of human bone marrow stromal cells. Neurosurgery 53:6977032003

20

Pereira RFHalford KWO'Hara MDLeeper DBSokolov BPPollard MD: Cultured adherent cells from marrow can serve as long-lasting precursor cells for bone, cartilage, and lung in irradiated mice. Proc Natl Acad Sci U S A 92:485748611995

21

Pereira RFO'Hara MDLaptev AVHalford KWPollard MDClass R: Marrow stromal cells as a source of progenitor cells for nonhematopoietic tissues in transgenic mice with a phenotype of osteogenesis imperfecta. Proc Natl Acad Sci U S A 95:114211471998

22

Pittenger MFMackay AMBeck SCJaiswal RKDouglas RMosca JD: Multilineage potential of adult human mesenchymal stem cells. Science 284:1431471999

23

Prockop DJ: Heritable osteoarthritis. Diagnosis and possible modes of cell and gene therapy. Osteoarthritis Cartilage 7:3643661999

24

Prockop DJ: Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 276:71741997

25

Seyfried DHan YLu DChen JBydon AChopp M: Improvement in neurological outcome after administration of atorvastatin following experimental intracerebral hemorrhage in rats. J Neurosurg 101:1041072004

26

Ujike HTakaki MKodama MKuroda S: Gene expression related to synaptogenesis, neuritogenesis, and MAP kinase in behavioral sensitization to psychostimulants. Ann NY Acad Sci 965:55672002

27

Villars FBordenave LBareille RAmedee J: Effect of human endothelial cells on human bone marrow stromal cell phenotype: role of VEGF. J Cell Biochem 79:6726852000

28

Xi GHua YBhasin RREnnis SRKeep RFHoff JT: Mechanisms of edema formation after intracerebral hemorrhage: effects of extravasated red blood cells on blood flow and blood-brain barrier integrity. Stroke 32:293229382001

29

Zhang LSchallert TZhang ZGJiang QArniego PLi Q: A test for detecting long-term sensorimotor dysfunction in the mouse after focal cerebral ischemia. J Neurosci Methods 117:2072142002

30

Zhang ZJiang QJiang FDing GZhang RWang L: In vivo magnetic resonance imaging tracks adult neural progenitor cell targeting of brain tumor. Neuroimage 23:2812872004

31

Zhang ZGZhang LJiang QChopp M: Bone marrow-derived endothelial progenitor cells participate in cerebral neovascularization after focal cerebral ischemia in the adult mouse. Circ Res 90:2842882002

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