Evaluation of clinical experience using cell-based therapies in patients with spinal cord injury: a systematic review

View More View Less
  • 1 Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania;
  • 2 Spectrum Research Inc., Tacoma, Washington;
  • 3 Department of Neurosurgery, University of Maryland, Baltimore, Maryland;
  • 4 Department of Neurosurgery, The Methodist Hospital, Houston, Texas;
  • 5 Department of Neurological Surgery, University of Miami, Florida;
  • 6 Department of Neurosurgery, University of Toronto, Ontario, Canada; and
  • 7 Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, Washington
Restricted access

Purchase Now

USD  $45.00

Spine - 1 year subscription bundle (Individuals Only)

USD  $369.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00
Print or Print + Online

Object

Using a systematic approach, the authors evaluated the current utilization, safety, and effectiveness of cellular therapies for traumatic spinal cord injuries (SCIs) in humans.

Methods

A systematic search and critical review of the literature published through mid-January 2012 was performed. Articles included in the search were restricted to the English language, studies with at least 10 patients, and those analyzing cellular therapies for traumatic SCI. Citations were evaluated for relevance using a priori criteria, and those that met the inclusion criteria were critically reviewed. Each article was then designated a level of evidence that was developed by the Oxford Centre for Evidence-Based Medicine.

Results

The initial literature search identified 651 relevant articles, which decreased to 350 after excluding case reports and reviews. Evaluation of articles at the title/abstract level, and later at the full-text level, limited the final article set to 12 papers. The following cellular therapies employed in humans with SCI are reviewed: bone marrow mesenchymal and hematopoietic stem cells (8 studies), olfactory ensheathing cells (2 studies), Schwann cells (1 study), and fetal neurogenic tissue (1 study). Overall the quality of the literature was very low, with 3 Grade III levels of evidence and 9 Grade IV studies.

Conclusions

Several different cellular-mediated strategies for adult SCI have been reported to be relatively safe with varying degrees of neurological recovery. However, the literature is of low quality and there is a need for improved preclinical studies and prospective, controlled clinical trials.

Abbreviations used in this paper:AIS = ASIA Impairment Scale; ASIA = American Spinal Injury Association; FIM = Functional Independence Measure; GM-CSF = granulocyte-macrophage colony-stimulating factor; MSC = mesenchymal stem cell; SCI = spinal cord injury; SSEP = somatosensory evoked potential; VAS = visual analog scale.

Spine - 1 year subscription bundle (Individuals Only)

USD  $369.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00

Contributor Notes

Address correspondence to: James S. Harrop, M.D., Thomas Jefferson University, 909 Walnut Street, Suite 300, Philadelphia, Pennsylvania 19107. email: james.harrop@jefferson.edu.

Please include this information when citing this paper: DOI: 10.3171/2012.5.AOSPINE12115.

  • 1

    Abe M, , Umehara F, , Kubota R, , Moritoyo T, , Izumo S, & Osame M: Activation of macrophages/microglia with the calcium-binding proteins MRP14 and MRP8 is related to the lesional activities in the spinal cord of HTLV-I associated myelopathy. J Neurol 246:358364, 1999

    • Search Google Scholar
    • Export Citation
  • 2

    Abouelfetouh A, , Kondoh T, , Ehara K, & Kohmura E: Morphological differentiation of bone marrow stromal cells into neuron-like cells after co-culture with hippocampal slice. Brain Res 1029:114119, 2004

    • Search Google Scholar
    • Export Citation
  • 3

    Alper J: Geron gets green light for human trial of ES cell-derived product. Nat Biotechnol 27:213214, 2009

  • 4

    Atkins D, , Briss P, , Eccles M, , Flottorp S, , Guyatt GH, & Harbour RT, : Systems for grading the quality of evidence and the strength of recommendations II: pilot study of a new system. BMC Health Services Research 5:25, 2005

    • Search Google Scholar
    • Export Citation
  • 5

    Bakshi A, , Barshinger AL, , Swanger SA, , Madhavani V, , Shumsky JS, & Neuhuber B, : Lumbar puncture delivery of bone marrow stromal cells in spinal cord contusion: a novel method for minimally invasive cell transplantation. J Neurotrauma 23:5565, 2006

    • Search Google Scholar
    • Export Citation
  • 6

    Barakat DJ, , Gaglani SM, , Neravetla SR, , Sanchez AR, , Andrade CM, & Pressman Y, : Survival, integration, and axon growth support of glia transplanted into the chronically contused spinal cord. Cell Transplant 14:225240, 2005

    • Search Google Scholar
    • Export Citation
  • 7

    Baron-Van Evercooren A, , Avellana-Adalid V, , Lachapelle F, & Liblau R: Schwann cell transplantation and myelin repair of the CNS. Mult Scler 3:157161, 1997

    • Search Google Scholar
    • Export Citation
  • 8

    Blight AR: Macrophages and inflammatory damage in spinal cord injury. J Neurotrauma 9:Suppl 1 S83S91, 1992

  • 9

    Burns AS, , Lee BS, , Ditunno JF Jr, & Tessler A: Patient selection for clinical trials: the reliability of the early spinal cord injury examination. J Neurotrauma 20:477482, 2003

    • Search Google Scholar
    • Export Citation
  • 10

    Callera F, & de Melo CM: Magnetic resonance tracking of magnetically labeled autologous bone marrow CD34+ cells transplanted into the spinal cord via lumbar puncture technique in patients with chronic spinal cord injury: CD34+ cells' migration into the injured site. Stem Cells Dev 16:461466, 2007

    • Search Google Scholar
    • Export Citation
  • 11

    Campbell PG, , Yadla S, , Malone J, , Maltenfort MG, , Harrop JS, & Sharan AD, : Complications related to instrumentation in spine surgery: a prospective analysis. Neurosurg Focus 31:4 E10, 2011

    • Search Google Scholar
    • Export Citation
  • 12

    Chen L, , Huang H, , Zhang J, , Zhang F, , Liu Y, & Xi H, : Short-term outcome of olfactory ensheathing cells transplantation for treatment of amyotrophic lateral sclerosis. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 21:961966, 2007

    • Search Google Scholar
    • Export Citation
  • 13

    Chernykh ER, , Stupak VV, , Muradov GM, , Sizikov MY, , Shevela EY, & Leplina OY, : Application of autologous bone marrow stem cells in the therapy of spinal cord injury patients. Bull Exp Biol Med 143:543547, 2007

    • Search Google Scholar
    • Export Citation
  • 14

    Cristante AF, , Barros-Filho TE, , Tatsui N, , Mendrone A, , Caldas JG, & Camargo A, : Stem cells in the treatment of chronic spinal cord injury: evaluation of somatosensitive evoked potentials in 39 patients. Spinal Cord 47:733738, 2009

    • Search Google Scholar
    • Export Citation
  • 15

    Fehlings MG, & Vawda R: Cellular treatments for spinal cord injury: the time is right for clinical trials. Neurotherapeutics 8:704720, 2011

    • Search Google Scholar
    • Export Citation
  • 16

    Féron F, , Perry C, , Cochrane J, , Licina P, , Nowitzke A, & Urquhart S, : Autologous olfactory ensheathing cell transplantation in human spinal cord injury. Brain 128:29512960, 2005

    • Search Google Scholar
    • Export Citation
  • 17

    FierceBiotech: FDA Places Geron Corporation (GERN)'s GRNOPC1 IND on Clinical Hold (http://www.fiercebiotech.com/press-releases/fda-places-geron-corporation-gern-sgrnopc1-ind-clinical-hold) [Accessed May 17, 2012]

    • Search Google Scholar
    • Export Citation
  • 18

    Frisén J, , Haegerstrand A, , Fried K, , Piehl F, , Cullheim S, & Risling M: Adhesive/repulsive properties in the injured spinal cord: relation to myelin phagocytosis by invading macrophages. Exp Neurol 129:183193, 1994

    • Search Google Scholar
    • Export Citation
  • 19

    Geisler FH, , Coleman WP, , Grieco G, & Poonian D: Measurements and recovery patterns in a multicenter study of acute spinal cord injury. Spine (Phila Pa 1976) 26:24 Suppl S68S86, 2001

    • Search Google Scholar
    • Export Citation
  • 20

    Geisler FH, , Coleman WP, , Grieco G, & Poonian D: The Sygen multicenter acute spinal cord injury study. Spine (Phila Pa 1976) 26:24 Suppl S87S98, 2001

    • Search Google Scholar
    • Export Citation
  • 21

    Harrop JS, , Maltenfort MG, , Geisler FH, , Coleman W, , Jones LA, & Wirth E, : Traumatic thoracic ASIA A examinations and potential for clinical trials. Spine (Phila Pa 1976) 34:25252529, 2009

    • Search Google Scholar
    • Export Citation
  • 22

    Harrop JS, , Naroji S, , Maltenfort MG, , Ratliff JK, , Tjoumakaris SI, & Frank B, : Neurologic improvement after thoracic, thoracolumbar, and lumbar spinal cord (conus medullaris) injuries. Spine (Phila Pa 1976) 36:2125, 2011

    • Search Google Scholar
    • Export Citation
  • 23

    Huang H, , Chen L, , Wang H, , Xi H, , Gou C, & Zhang J, : Safety of fetal olfactory ensheathing cell transplantation in patients with chronic spinal cord injury. A 38-month follow-up with MRI. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 20:439443, 2006

    • Search Google Scholar
    • Export Citation
  • 24

    Jendelová P, , Herynek V, , Urdzíková L, , Glogarová K, , Kroupová J, & Andersson B, : Magnetic resonance tracking of transplanted bone marrow and embryonic stem cells labeled by iron oxide nanoparticles in rat brain and spinal cord. J Neurosci Res 76:232243, 2004

    • Search Google Scholar
    • Export Citation
  • 25

    Jones LA, , Lammertse DP, , Charlifue SB, , Kirshblum SC, , Apple DF, & Ragnarsson KT, : A phase 2 autologous cellular therapy trial in patients with acute, complete spinal cord injury: pragmatics, recruitment, and demographics. Spinal Cord 48:798807, 2010

    • Search Google Scholar
    • Export Citation
  • 26

    Kaur C, , Yong ES, & Ling EA: Studies of activated microglia and macrophages in lumbosacral spinal cord following an intraperitoneal injection of 6-aminonicotinamide into adult rats. Histol Histopathol 8:699707, 1993

    • Search Google Scholar
    • Export Citation
  • 27

    Keirstead HS, , Nistor G, , Bernal G, , Totoiu M, , Cloutier F, & Sharp K, : Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci 25:46944705, 2005

    • Search Google Scholar
    • Export Citation
  • 28

    King-Robson J: Encouraging regeneration in the central nervous system: is there a role for olfactory ensheathing cells?. Neurosci Res 69:263275, 2011

    • Search Google Scholar
    • Export Citation
  • 29

    Kirshblum S, , Millis S, , McKinley W, & Tulsky D: Late neurologic recovery after traumatic spinal cord injury. Arch Phys Med Rehabil 85:18111817, 2004

    • Search Google Scholar
    • Export Citation
  • 30

    Kishk NA, , Gabr H, , Hamdy S, , Afifi L, , Abokresha N, & Mahmoud H, : Case control series of intrathecal autologous bone marrow mesenchymal stem cell therapy for chronic spinal cord injury. Neurorehabil Neural Repair 24:702708, 2010

    • Search Google Scholar
    • Export Citation
  • 31

    Knoller N, , Auerbach G, , Fulga V, , Zelig G, , Attias J, & Bakimer R, : Clinical experience using incubated autologous macrophages as a treatment for complete spinal cord injury: phase I study results. J Neurosurg Spine 3:173181, 2005

    • Search Google Scholar
    • Export Citation
  • 32

    Kumar AA, , Kumar SR, , Narayanan R, , Arul K, & Baskaran M: Autologous bone marrow derived mononuclear cell therapy for spinal cord injury: a phase I/II clinical safety and primary efficacy data. Exp Clin Transplant 7:241248, 2009

    • Search Google Scholar
    • Export Citation
  • 33

    Lavdas AA, , Papastefanaki F, , Thomaidou D, & Matsas R: Schwann cell transplantation for CNS repair. Curr Med Chem 15:151160, 2008

  • 34

    Lebude B, , Yadla S, , Albert T, , Anderson DG, , Harrop JS, & Hilibrand A, : Defining “complications” in spine surgery: neurosurgery and orthopedic spine surgeons' survey. J Spinal Disord Tech 23:493500, 2010

    • Search Google Scholar
    • Export Citation
  • 35

    Lima C, , Escada P, , Pratas-Vital J, , Branco C, , Arcangeli CA, & Lazzeri G, : Olfactory mucosal autografts and rehabilitation for chronic traumatic spinal cord injury. Neurorehabil Neural Repair 24:1022, 2010

    • Search Google Scholar
    • Export Citation
  • 36

    Lima C, , Pratas-Vital J, , Escada P, , Hasse-Ferreira A, , Capucho C, & Peduzzi JD: Olfactory mucosa autografts in human spinal cord injury: a pilot clinical study. J Spinal Cord Med 29:191206, 2006

    • Search Google Scholar
    • Export Citation
  • 37

    Mackay-Sim A, , Féron F, , Cochrane J, , Bassingthwaighte L, , Bayliss C, & Davies W, : Autologous olfactory ensheathing cell transplantation in human paraplegia: a 3-year clinical trial. Brain 131:23762386, 2008

    • Search Google Scholar
    • Export Citation
  • 38

    Mackay-Sim A, & St John JA: Olfactory ensheathing cells from the nose: clinical application in human spinal cord injuries. Exp Neurol 229:174180, 2011

    • Search Google Scholar
    • Export Citation
  • 39

    Marino RJ, , Ditunno JF Jr, , Donovan WH, & Maynard F Jr: Neurologic recovery after traumatic spinal cord injury: data from the Model Spinal Cord Injury Systems. Arch Phys Med Rehabil 80:13911396, 1999

    • Search Google Scholar
    • Export Citation
  • 40

    Mayor S: First patient enters trial to test safety of stem cells in spinal injury. BMJ 341:c5724, 2010

  • 41

    Mehta T, , Feroz A, , Thakkar U, , Vanikar A, , Shah V, & Trivedi H: Subarachnoid placement of stem cells in neurological disorders. Transplant Proc 40:11451147, 2008

    • Search Google Scholar
    • Export Citation
  • 42

    Mezey E, , Chandross KJ, , Harta G, , Maki RA, & McKercher SR: Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science 290:17791782, 2000

    • Search Google Scholar
    • Export Citation
  • 43

    Nasser R, , Yadla S, , Maltenfort MG, , Harrop JS, , Anderson DG, & Vaccaro AR, : Complications in spine surgery. A review. J Neurosurg Spine 13:144157, 2010

    • Search Google Scholar
    • Export Citation
  • 44

    Ogawa Y, , Sawamoto K, , Miyata T, , Miyao S, , Watanabe M, & Nakamura M, : Transplantation of in vitro-expanded fetal neural progenitor cells results in neurogenesis and functional recovery after spinal cord contusion injury in adult rats. J Neurosci Res 69:925933, 2002

    • Search Google Scholar
    • Export Citation
  • 45

    Okamura RM, , Lebkowski J, , Au M, , Priest CA, , Denham J, & Majumdar AS: Immunological properties of human embryonic stem cell-derived oligodendrocyte progenitor cells. J Neuroimmunol 192:134144, 2007

    • Search Google Scholar
    • Export Citation
  • 46

    Pal R, , Venkataramana NK, , Bansal A, , Balaraju S, , Jan M, & Chandra R, : Ex vivo-expanded autologous bone marrow-derived mesenchymal stromal cells in human spinal cord injury/paraplegia: a pilot clinical study. Cytotherapy 11:897911, 2009

    • Search Google Scholar
    • Export Citation
  • 47

    Park SS, , Byeon YE, , Ryu HH, , Kang BJ, , Kim Y, & Kim WH, : Comparison of canine umbilical cord blood-derived mesenchymal stem cell transplantation times: Involvement of astrogliosis, inflammation, intracellular actin cytoskeleton pathways, and neurotrophin. Cell Transplant [epub ahead of print], 2011

    • Search Google Scholar
    • Export Citation
  • 48

    Popovich PG, , Guan Z, , Wei P, , Huitinga I, , van Rooijen N, & Stokes BT: Depletion of hematogenous macrophages promotes partial hindlimb recovery and neuroanatomical repair after experimental spinal cord injury. Exp Neurol 158:351365, 1999

    • Search Google Scholar
    • Export Citation
  • 49

    Rabinovich SS, , Seledtsov VI, , Poveschenko OV, , Senuykov VV, , Taraban VY, & Yarochno VI, : Transplantation treatment of spinal cord injury patients. Biomed Pharmacother 57:428433, 2003

    • Search Google Scholar
    • Export Citation
  • 50

    Ramón-Cueto A, & Muñoz-Quiles C: Clinical application of adult olfactory bulb ensheathing glia for nervous system repair. Exp Neurol 229:181194, 2011

    • Search Google Scholar
    • Export Citation
  • 51

    Ramón-Cueto A, & Nieto-Sampedro M: Regeneration into the spinal cord of transected dorsal root axons is promoted by ensheathing glia transplants. Exp Neurol 127:232244, 1994

    • Search Google Scholar
    • Export Citation
  • 52

    Saberi H, , Firouzi M, , Habibi Z, , Moshayedi P, , Aghayan HR, & Arjmand B, : Safety of intramedullary Schwann cell transplantation for postrehabilitation spinal cord injuries: 2-year follow-up of 33 cases. Clinical article. J Neurosurg Spine 15:515525, 2011

    • Search Google Scholar
    • Export Citation
  • 53

    Saberi H, , Moshayedi P, , Aghayan HR, , Arjmand B, , Hosseini SK, & Emami-Razavi SH, : Treatment of chronic thoracic spinal cord injury patients with autologous Schwann cell transplantation: an interim report on safety considerations and possible outcomes. Neurosci Lett 443:4650, 2008

    • Search Google Scholar
    • Export Citation
  • 54

    Schwartz M, , Lazarov-Spiegler O, , Rapalino O, , Agranov I, , Velan G, & Hadani M: Potential repair of rat spinal cord injuries using stimulated homologous macrophages. Neurosurgery 44:10411046, 1999

    • Search Google Scholar
    • Export Citation
  • 55

    Schwartz M, & Yoles E: Macrophages and dendritic cells treatment of spinal cord injury: from the bench to the clinic. Acta Neurochir Suppl 93:147150, 2005

    • Search Google Scholar
    • Export Citation
  • 56

    Seledtsova GV, , Rabinovich SS, , Belogorodtsev SN, , Parlyuk OV, , Seledtsov VI, & Kozlov VA: Delayed results of transplantation of fetal neurogenic tissue in patients with consequences of spinal cord trauma. Bull Exp Biol Med 149:530533, 2010

    • Search Google Scholar
    • Export Citation
  • 57

    Sharp J, , Frame J, , Siegenthaler M, , Nistor G, & Keirstead HS: Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants improve recovery after cervical spinal cord injury. Stem Cells 28:152163, 2010

    • Search Google Scholar
    • Export Citation
  • 58

    Song S, , Song S, , Zhang H, , Cuevas J, & Sanchez-Ramos J: Comparison of neuron-like cells derived from bone marrow stem cells to those differentiated from adult brain neural stem cells. Stem Cells Dev 16:747756, 2007

    • Search Google Scholar
    • Export Citation
  • 59

    Steeves JD, , Kramer JK, , Fawcett JW, , Cragg J, , Lammertse DP, & Blight AR, : Extent of spontaneous motor recovery after traumatic cervical sensorimotor complete spinal cord injury. Spinal Cord 49:257265, 2011

    • Search Google Scholar
    • Export Citation
  • 60

    Strauss S: Geron trial resumes, but standards for stem cell trials remain elusive. Nat Biotechnol 28:989990, 2010

  • 61

    Stroncek DF, , Clay ME, , Petzoldt ML, , Smith J, , Jaszcz W, & Oldham FB, : Treatment of normal individuals with granulocytecolony-stimulating factor: donor experiences and the effects on peripheral blood CD34+ cell counts and on the collection of peripheral blood stem cells. Transfusion 36:601610, 1996

    • Search Google Scholar
    • Export Citation
  • 62

    Syková E, , Homola A, , Mazanec R, , Lachmann H, , Konrádová SL, & Kobylka P, : Autologous bone marrow transplantation in patients with subacute and chronic spinal cord injury. Cell Transplant 15:675687, 2006

    • Search Google Scholar
    • Export Citation
  • 63

    Syková E, , Jendelová P, , Urdzíková L, , Lesný P, & Hejcl A: Bone marrow stem cells and polymer hydrogels—two strategies for spinal cord injury repair. Cell Mol Neurobiol 26:11131129, 2006

    • Search Google Scholar
    • Export Citation
  • 64

    Tetzlaff W, , Okon EB, , Karimi-Abdolrezaee S, , Hill CE, , Sparling JS, & Plemel JR, : A systematic review of cellular transplantation therapies for spinal cord injury. J Neurotrauma 28:16111682, 2011

    • Search Google Scholar
    • Export Citation
  • 65

    Vaquero J, & Zurita M: Bone marrow stromal cells for spinal cord repair: a challenge for contemporary neurobiology. Histol Histopathol 24:107116, 2009

    • Search Google Scholar
    • Export Citation
  • 66

    Wright JG, , Swiontkowski MF, & Heckman JD: Introducing levels of evidence to the journal. J Bone Joint Surg Am 85-A:13, 2003

  • 67

    Yadla S, , Malone J, , Campbell PG, , Maltenfort MG, , Sharan AD, & Harrop JS, : Preoperative diagnosis and early complications in thoracolumbar spine surgery: a single center prospective study. J Spinal Disord Tech 24:E16E20, 2011

    • Search Google Scholar
    • Export Citation
  • 68

    Yang Q, , Mu J, , Li Q, , Li A, , Zeng Z, & Yang J, : A simple and efficient method for deriving neurospheres from bone marrow stromal cells. Biochem Biophys Res Commun 372:520524, 2008

    • Search Google Scholar
    • Export Citation
  • 69

    Yoon SH, , Shim YS, , Park YH, , Chung JK, , Nam JH, & Kim MO, : Complete spinal cord injury treatment using autologous bone marrow cell transplantation and bone marrow stimulation with granulocyte macrophage-colony stimulating factor: Phase I/II clinical trial. Stem Cells 25:20662073, 2007

    • Search Google Scholar
    • Export Citation

Metrics

All Time Past Year Past 30 Days
Abstract Views 546 307 20
Full Text Views 152 18 0
PDF Downloads 140 11 0
EPUB Downloads 0 0 0