Journal of ISSN: 2475-5540 JSRT

Stem Cell Research & Therapeutics
Mini Review
Volume 1 Issue 4 - 2016
One Step at a Time, Stem Cell Therapy for Traumatic Brain Injury Needs Two More Breakthroughs
Gajavelli Shyam*
Associate scientist, University of Miami, USA
Received: May 18, 2016 | Published: September 16, 2016
*Corresponding author: Gajavelli Shyam, Associate scientist, University of Miami, 1095 NW 14th Terrace Lois Pope LIFE Center, Miami, FL 33136, USA, Email:
Citation: Shyam G (2016) One Step at a Time, Stem Cell Therapy for Traumatic Brain Injury Needs Two More Breakthroughs. J Stem Cell Res Ther 1(4): 00027. DOI: 10.15406/jsrt.2016.01.00027


Traumatic brain injuries often result in disability in survivors. Unresolved inflammation and ongoing neurodegeneration underlies the disability. Human neural stem cells (NSCs) are attractive candidates that can address both issues at once. Despite several preclinical studies and start-up companies over the past two decades, the approach is not yet in the clinic. In this mini review, I present two steps that brought the NSCs from lab to Phase I/II trials and final two breakthroughs that may be necessary to facilitate clinical application.

Keywords: Traumatic brain injury; Neurodegeneration; Human neural stem cells; Firearm injury; Neuro imaging


Firearm injury is a serious public health problem in the United States (US) costing more than $70-75 billion annually [1,2]. Non-fatal gunshot injuries in the US have increased from 20.5 per 100,000 Americans in 2002 to 23.7 per 100,000 by 2011, mainly due to increased assaults [3]. Despite increasing incidence, timely neurosurgical intervention aided with improved neuro imaging and advances in acute trauma management have lowered the firearm fatality rate [4-6]. Thus, among the estimated 5.3 million people living in the US with traumatic brain injury (TBI)-related disability, the proportion of gun-shot wound survivors has been rising steadily [3,7-11]. Among head injuries, penetrating injuries (PTBI) are associated with the worst outcomes [12,13], and no effective restorative treatment beyond physical therapy is currently available to mitigate post-TBI disability [12-14]. Therefore, there is an urgent need to explore additional treatment options to address long term TBI related disabilities. Studies with preclinical models have demonstrated that failure of injury-induced regenerative neurogenesis; chronic inflammation and atrophy underlie poor outcomes [15-17]. Loss of neurons and consequent brain atrophy is a consistent neuro pathological finding in TBI survivors and may underlie long-term functional deficits, resulting in reduced executive and integrative capability [18-20]. Human PTBI neuro pathological findings support neuronal and axonal loss with significant brain atrophy [21]. The milestones in neural stem cell (NSC) research were outlined in a review by Gage and Temple, pioneers of the field [22]. NSCs afford the plasticity to generate, repair, and change nervous system function thus are of great interest to basic scientists as well as clinicians. NSCs have not blossomed into a therapeutic as yet and in this article some the issues that underlies the dormancy are discussed. The cell therapy field needed to address four main issues before clinical trials can be started. Firstly, production of the cell therapy candidate under good manufacturing conditions (GMP), second discovery of efficient immunosuppression, third demonstration of therapeutic benefit under controlled conditions. Three decades of basic science has managed to address first two issues.

Step 1 Cell therapy candidate

Neural stem cells have several characteristics that make them ideal candidates for brain repair, including a relatively high potential for neuronal differentiation [1,23-25]. Several preclinical studies have evaluated the efficacy of rodent neural precursor cells in TBI rodent models [22,26-30]. The culturing NSCs in vitro started as an attempt to grow multipotent embryonic cortical tissue (the word neural stem cells was not yet coined) and successfully accomplished in 1989 at the University of Miami [31]. This work evolved when Martin Raff, a Canadian born Boston neurologist decided to move to England and chose to leave the United States (US) than fight in Vietnam War and to pursue immunology [32]. After elucidating the properties of T-cells and B-cells, in a bid to stay on a new research plan was hatched. It was to raise antibodies against cells of the nervous system and use them to distinguish and separate the different cell types so that their development and interactions could be studied, albeit mainly in a culture dish [32]. One his students was Sally Temple, she worked on have a cell-intrinsic mechanism that helps determine when precursor cells should stop dividing and differentiate into oligodendrocytes. She published her work during her brief stop at University of Miami before heading off to Albany, NY from where she still contributes to the NSC field [22,33]. Attempts to identify the growth factors required for culturing these cells was pioneered at NIH under Ron McKay. Initially the group misidentified NGF [34,35] as a NSC growth factor only to come back later with the right one [36]. This set stage for two companies namely Neural stem Inc., and Stem cells Inc. Both have produced stable cells under good manufacturing practice “GMP standard” conditions, secured FDA approval to use the cells in human clinical trials. In the past decade, Neural stem Inc. had developed NSI-566, an epigenetically expanded bank of NSC derived from 8-week human fetal spinal cord, which is not on the Federal moratorium list for funding [37]. These cells have been subject to extensive preclinical safety testing and characterization, by multiple independent labs with multiple immunosuppression regimens [38-44]. The cells are produced under stable good manufacturing practice “GMP standard” conditions, and have been recently tested in several animal models. They are subject of three ongoing FDA approved clinical trials including a Phase II study for amyotrophic lateral sclerosis (ALS), a trial for ischemic stroke, and a Phase I study for chronic spinal cord injury [26]. As of 2015, a total of 49 ALS patients have received NSI-566 cells. Both the cells and surgery were well tolerated and the ALS studies reported a 47% responder rate with decline in disease progression and improved grip strength. Stem cells inc., on the other hand lost a patent dispute to NSI and recently closed operations.

Step 2 Immunosuppression

Transplantation of the cells conferred benefits such as restoration of injured neuronal morphology [45] and cognitive function [46] even without immunosuppression. Transient immunosuppression was shown to be sufficient to support engraftment and transplanted derived neurons were reportedly present 6 months post transplantation [47]. However, no data quantifying either engraftment or behavior modification were presented. Such studies were limited by cyclosporine mediated immunosuppression which resulted in persistence of barriers to engraftment and demonstration of effectiveness of the approach [48-50]. The initial optimism was replaced by skepticism if the therapeutic potential of neural stem cells: greater in people's perception than in their brains? [51,52]. The US Food and Drug Administration (FDA; Rockville, MD) guidelines on preclinical assessment of cell therapies in the publication “Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products” [53,54]. A review of literature shows human cell therapy in rat TBI that measure cognitive benefit have not addressed donor cell fate past one-month post-transplantation [1,55]. Further the experts in the field recommended that 8‑week survival period prior to assessments would allow sufficient time for differentiation and integration of human neural stem cells with the host and possibly validate the presumed mechanism of action [1,26]. The successful preclinical ALS, SCI and stroke studies [40,41,44,56] have employed a different immunosuppression technique that was pioneered by Hefferan et al. [40]. This technique relies on three agents namely: mycophenylate mofetil, tacrolimus and methyl prednisolone. The combination has been found to be superior to cyclosporine, a standard immunosuppressant between 1999-2012.

Step 3 Mechanism of action

However, due to the lack of exact mechanism of action still precludes attempts to move neural stem cell therapy to the clinic [26]. Paul Lu et al. [41] demonstrated the mechanism of regeneration in spinal cord injury models [41]. Axonal growth was partially dependent on mammalian target of rapamycin (mTOR), but not Nogo signaling. Grafted neurons supported formation of electrophysiological relays across sites of complete spinal transection, resulting in functional recovery. The recovery was lost subsequent to re-transection of the spinal cord. With modern sophisticated methods such as functional connectivity under optogenetic control would provide necessary evidence for mechanism of action [57].

Step 4 safety

Variety of companies have derived and developed human fetal neural stem cells [58]. Some companies have closed (REF JSRT-16-NWS-125), others made little progress, while Neural stem Inc., has remained viable. However as not NSCs are equal is evident from various outcomes of the transplantations. At least three adverse reaction cases have been reported to date [59-61]. In contrast cells from Stem cells Inc, Neural stem Inc and in an Italian study have been found to be safe [42,58,62]. The difference may be attributed to quality of cells. With unregulated clinical use rampant all over the World [58,63-66], the research scientists need to heed the advice given by Prof. Knoepfler [67].

Among the non-neural stem cells from which NSCs have been derived, AMP have exhibited the best neural differentiation potential [68]. Mesenchymal origin neural stem cells (mNSCs) and AMP derived NSCs (AM-NSCs) differentiated, expressed some neural markers, and were associated with cognitive benefits early after transplantation, post-TBI. However, AM-NSCs did not survive in the brain injury site 1 month after transplantation [69]. Few reports have demonstrated integration of such cells into host tissues, thus suggesting this cell type to be a poor candidate for cell replacement [70-73].

A recent study with athymic rat TBI and hNSCs ~38% of the transplanted cells expressed NeuN [74]. The duration of differentiation of hNSCs into NeuN positive cells is consistent with a published report that showed ~6-8 weeks were sufficient to induce transplant derived neurogenesis [1,75].

Transplantation of viable fetal neural progenitor cells (as early as 24h post TBI) attenuated host neuronal degeneration (as assessed on day 6 post transplantation), also guided host microglia/macrophages towards an anti-inflammation phenotype indicating that a potentially beneficial effect of progenitor cell transplantation on adjacent host cells [30,76-78].

In other TBI and stroke models, cells have been delivered via intravenous (IV), intra-arterial carotid (IAC) or intraparenchymal (IP) injections. However, IV administration causes loss of the majority (~95%) of the cells during lung passage [55,79-81], whereas IAC injection carries the risk of causing embolic brain infarction and fails to deliver sufficient cells across the vascular wall barrier to the brain parenchyma, which is the major barrier for putative clinical use of this route. Engraftment after IAC injection is also dependent on cell type and adhesion molecule expression. IAC has been developed with bone marrow MSCs into a clinical trial for stroke [82,83]. However, in all TBI studies exploring human cell therapies with neural or non-neural origin hNSCs/progenitors no engraftment has yet been detected with either IV or IAC [84,85]. Direct transplantation of hNSCs to replace damaged neural networks may be a viable approach in the treatment of severe TBI. According to “The International Society for Stem Cell Research and Center for Biologics Evaluation and Research/Office of Cellular, Tissue and Gene Therapies” 54 FDA guidelines, translation of cell transplantation approach in TBI requires evidence supporting: (1) lack of hNSCs tumorigenecity in TBI models, (2) cell dose dependence of behavior alterations in TBI, (3) best site and time for transplantation after TBI, and lastly (4) to establish feasibility, and scalability of the approach to both normal and TBI animals with longer gyrencephalic brains, such as pig or primate [53,54, 86].


In conclusion albeit the NSC holds great promise the final two steps described above hold key to application in the clinic, To help with this The International Society for Stem Cell Research (ISSCR)’ has presented its 2016 Guidelines for Stem Cell Research and Clinical Translation. The 2016 guidelines reflect the revision and extension of two past sets of guidelines and demand rigor, oversight, and transparency in all aspects of practice, providing confidence to practitioners and public alike that stem cell science can proceed efficiently and remain responsive to public and patient interests [87-89].


  1. Gold EM, Su D, Lopez Velazquez L, Haus DL, Perez H, et al. (2013) Functional assessment of long-term deficits in rodent models of traumatic brain injury. Regen Med 8(4): 483-516.
  2. Tasigiorgos S, Economopoulos KP, Winfield RD, Sakran JV (2015) Firearm Injury in the United States: An Overview of an Evolving Public Health Problem. J Am Coll Surg 221(6): 1005-1014.
  3. Jena AB, Sun EC, Prasad V (2014) Does the declining lethality of gunshot injuries mask a rising epidemic of gun violence in the United States? J Gen Intern Med 29(7): 1065-1069.
  4. Joseph B, Aziz H, Pandit V, Kulvatunyou N, O Keeffe T, et al. (2014) Improving survival rates after civilian gunshot wounds to the brain. J Am Coll Surg 218(1): 58-65.
  5. Lin DJ, Lam FC, Siracuse JJ, Thomas A, Kasper EM (2012) "Time is brain" the Gifford factor or: Why do some civilian gunshot wounds to the head do unexpectedly well? A case series with outcomes analysis and a management guide. Surg Neurol Int 3: 98.
  6. Young NH, Andrews PJ (2008) Developing a prognostic model for traumatic brain injury--a missed opportunity? PLoS medicine 5(8): e168.
  7. Corrigan JD, Selassie AW, Orman JA (2010) The epidemiology of traumatic brain injury. The Journal of head trauma rehabilitation 25(2): 72-80.
  8. Faul M XL, Wald MM, Coronado VG (2010) Traumatic brain injury in the United States: emergency department visits, hospitalizations, and deaths. Centers for Disease Control and Prevention, Atlanta, GA, USA, pp. 61.
  9. Gressot LV, Chamoun RB, Patel AJ, Valadka AB, Suki D, et al. (2014) Predictors of outcome in civilians with gunshot wounds to the head upon presentation. J Neurosurg 121(3): 645-652.
  10. Langlois JA, Rutland Brown W, Wald MM (2006) The epidemiology and impact of traumatic brain injury: a brief overview. J Head Trauma Rehabil 21(5): 375-378.
  11. Rosenfeld JV, Bell RS, Armonda R (2015) Current concepts in penetrating and blast injury to the central nervous system. World J Surg 39(6): 1352-1362.
  12. Khan MB, Kumar R, Irfan FB, Irfan AB, Bari ME (2014) Civilian craniocerebral gunshot injuries in a developing country: presentation, injury characteristics, prognostic indicators, and complications. World Neurosurg 82(1-2): 14-19.
  13. Pruitt B (2001) Part 2: Prognosis in penetrating brain injury. J Trauma 51(2 Suppl): S44-S86.
  14. Winn HR (2011) Youmans Neurological Surgery, 4-Volume Set, 6th Edition. Canada, USA, pp. 4960.
  15. Bramlett HM, Dietrich WD (2002) Quantitative structural changes in white and gray matter 1 year following traumatic brain injury in rats. Acta Neuropathol 103(6): 607-614.
  16. Kernie SG, Parent JM (2010) Forebrain neurogenesis after focal Ischemic and traumatic brain injury. Neurobiol Dis 37(2): 267-274.
  17. Richardson RM, Sun D, Bullock MR (2007) Neurogenesis after traumatic brain injury. Neurosurg Clin N Am 18(10): 169-181.
  18. Lozano D, Gonzales Portillo GS, Acosta S, de la Pena I, Tajiri N, et al. (2015) Neuroinflammatory responses to traumatic brain injury: etiology, clinical consequences, and therapeutic opportunities. Neuropsychiatr Dis Treat 11: 97-106.
  19. Maxwell WL, MacKinnon MA, Stewart JE, Graham DI (2010) Stereology of cerebral cortex after traumatic brain injury matched to the Glasgow outcome score. Brain 133: 139-160.
  20. Ramlackhansingh AF, Brooks DJ, Greenwood RJ, Bose SK, Turkheimer FE, et al. (2011) Inflammation after trauma: microglial activation and traumatic brain injury. Ann Neurol 70(3): 374-383.
  21. Oehmichen M, Meissner C (2009) Routine techniques in forensic neuropathology as demonstrated by gunshot injury to the head. Leg Med 11(Suppl 1): S50-S53.
  22. Gage FH, Temple S (2013) Neural stem cells: generating and regenerating the brain. Neuron 80(3): 588-601.
  23. Lemmens R, Steinberg GK (2013) Stem cell therapy for acute cerebral injury: what do we know and what will the future bring? Curr Opin Neurol 26(6): 617-625.
  24. Okano H (2002) Stem cell biology of the central nervous system. J Neurosci Res 69(6): 698-707.
  25. Pincus DW, Goodman RR, Fraser RA, Nedergaard M, Goldman SA (1998) Neural stem and progenitor cells: a strategy for gene therapy and brain repair. Neurosurgery 42(4): 858-867.
  26. Steinbeck JA, Studer L (2015) Moving stem cells to the clinic: potential and limitations for brain repair. Neuron 86(1): 187-206.
  27. Rolfe A, Sun D (2015) Stem Cell Therapy in Brain Trauma: Implications for Repair and Regeneration of Injured Brain in Experimental TBI Models. In: Kobeissy FH (Ed.), Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects. CRC Press/Taylor & Francis, USA.
  28. Kochanek PM, Jackson TC, Ferguson NM, Carlson SW, Simon DW, et al. (2015) Emerging therapies in traumatic brain injury. Semin Neurol 35(1): 83-100.
  29. Gennai S, Monsel A, Hao Q, Liu J, Gudapati V, et al. (2015) Cell-based therapy for traumatic brain injury. Br J Anaesth 115(2): 203-212.
  30. Gao J, Grill RJ, Dunn TJ, Bedi S, Labastida JA, et al. (2016) Human neural stem cell transplantation-mediated alteration of microglial/macrophage phenotypes after traumatic brain injury. Cell Transplant.
  31. Temple S (1989) Division and differentiation of isolated CNS blast cells in microculture. Nature 340(6233): 471-473.
  32. Squire LR (2006) The history of neuroscience in autobiography. Volume 5, Academic Press, USA.
  33. Temple S, Qian X (1996) Vertebrate neural progenitor cells: subtypes and regulation. Curr Opin Neurobiol 6(1): 11-17.
  34. Cattaneo E, McKay R (1991) Identifying and manipulating neuronal stem cells. Trends Neurosci 14(8): 338-340.
  35. Cattaneo E, McKay R (1990) Proliferation and differentiation of neuronal stem cells regulated by nerve growth factor. Nature 347(6295): 762-765.
  36. Johe KK, Hazel TG, Muller T, Dugich Djordjevic MM, McKay RD (1996) Single factors direct the differentiation of stem cells from the fetal and adult central nervous system. Genes Dev 10(24): 3129-3140.
  37. Guo X, Johe K, Molnar P, Davis H, Hickman J (2010) Characterization of a human fetal spinal cord stem cell line, NSI-566RSC, and its induction to functional motoneurons. J Tissue Eng Regen Med 4(3): 181-193.
  38. Feldman EL, Boulis NM, Hur J, Johe K, Rutkove SB, et al. (2014) Intraspinal neural stem cell transplantation in amyotrophic lateral sclerosis: phase 1 trial outcomes. Ann Neurol 75(3): 363-373.
  39. Glass JD, Boulis NM, Johe K, Rutkove SB, Federici T, et al. (2012) Lumbar intraspinal injection of neural stem cells in patients with amyotrophic lateral sclerosis: results of a phase I trial in 12 patients. Stem cells 30(6): 1144-1151.
  40. Hefferan MP, Galik J, Kakinohana O, Sekerkova G, Santucci C, et al. (2012) Human neural stem cell replacement therapy for amyotrophic lateral sclerosis by spinal transplantation. PloS one 7(8): e42614.
  41. Lu P, Wang Y, Graham L, McHale K, Gao M, et al. (2012) Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell 150(6): 1264-1273.
  42. Riley J, Federici T, Polak M, Kelly C, Glass J, et al. (2012) Intraspinal stem cell transplantation in amyotrophic lateral sclerosis: a phase I safety trial, technical note, and lumbar safety outcomes. Neurosurgery 71(2): 405-416.
  43. Riley J, Glass J, Feldman EL, Polak M, Bordeau J, et al. (2014) Intraspinal stem cell transplantation in amyotrophic lateral sclerosis: a phase I trial, cervical microinjection, and final surgical safety outcomes. Neurosurgery 74(1): 77-87.
  44. Tajiri N, Quach DM, Kaneko Y, Wu S, Lee D, et al. (2014) Behavioral and histopathological assessment of adult ischemic rat brains after intracerebral transplantation of NSI-566RSC cell lines. PloS one 9(3): e91408.
  45. Tsyb AF, Yuzhakov VV, Roshal' LM, Sukhikh GT, Konoplyannikov AG, et al. (2009). Morphofunctional study of the therapeutic efficacy of human mesenchymal and neural stem cells in rats with diffuse brain injury. Bull Exp Biol Med 147(1): 132-146.
  46. Roshal LM, Tzyb AF, Pavlova LN, Soushkevitch GN, Semenova JB, et al. (2009) Effect of cell therapy on recovery of cognitive functions in rats during the delayed period after brain injury. Bull Exp Biol Med 148(1): 140-147.
  47. Wennersten A, Holmin S, Al Nimer F, Meijer X, Wahlberg LU, et al. (2006) Sustained survival of xenografted human neural stem/progenitor cells in experimental brain trauma despite discontinuation of immunosuppression. Exp Neurol 199(2): 339-347.
  48. Lee DH, Lee JY, Oh BM, Phi JH, Kim SK, et al. (2013) Functional recovery after injury of motor cortex in rats: effects of rehabilitation and stem cell transplantation in a traumatic brain injury model of cortical resection. Childs Nerv Syst 29(3): 403-411.
  49. Oliveira AAD, SJ Hurtado JDC (2016) Neural stem cell transplantation and mechanisms for functional recovery. J Stem Cell Res Ther 1(2): 12.
  50. Skardelly M, Gaber K, Burdack S, Scheidt F, Schuhmann MU, et al. (2014). Transient but not permanent benefit of neuronal progenitor cell therapy after traumatic brain injury: potential causes and translational consequences. Front Cell Neurosci 8: 318.
  51. Cattaneo E, Bonfanti L (2014) Therapeutic potential of neural stem cells: greater in people's perception than in their brains? Front Neurosci 8: 79.
  52. Rossi F, Cattaneo E (2002) Opinion: neural stem cell therapy for neurological diseases: dreams and reality. Nat Rev Neurosci 3(5): 401-409.
  53. Bailey AM, Mendicino M, Au P (2014) An FDA perspective on preclinical development of cell-based regenerative medicine products. Nat Biotechnol 32(8): 721-723.
  54. OCTGT C (2013) Guidance for industry preclinical assessment of investigational cellular and gene therapy products. US Department of Health and Human Services Food and Drug Administration, Silver Spring, 10903 New Hampshire Avenue, USA, MD 20993.
  55. Chang J, Phelan M, Cummings BJ (2015) A meta-analysis of efficacy in pre-clinical human stem cell therapies for traumatic brain injury. Exp Neurol 273: 225-233.
  56. Xu L, Ryugo DK, Pongstaporn T, Johe K, Koliatsos VE (2009) Human neural stem cell grafts in the spinal cord of SOD1 transgenic rats: differentiation and structural integration into the segmental motor circuitry. J Comp Neurol 514(4): 297-309.
  57. Steinbeck JA, Jaiswal MK, Calder EL, Kishinevsky S, Weishaupt A, et al. (2016) Functional connectivity under optogenetic control allows modeling of human neuromuscular disease. Cell Stem Cell 18(1): 134-143.
  58. Trounson A, Mc Donald C (2015) Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell 17(1): 11-22.
  59. Amariglio N, Hirshberg A, Scheithauer BW, Cohen Y, Loewenthal R, et al. (2009) Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Med 6(2): e1000029.
  60. Berkowitz AL, Miller MB, Mir SA, Cagney D, Chavakula V, et al. (2016) Glioproliferative lesion of the spinal cord as a complication of "stem-cell tourism". N Engl J Med 375(2): 196-198.
  61. Thirabanjasak D, Tantiwongse K, Thorner PS (2010) Angiomyeloproliferative lesions following autologous stem cell therapy. J Am Soc Nephrol 21(7): 1218-1222.
  62. Mazzini L, Gelati M, Profico DC, Sgaravizzi G, Projetti Pensi M, et al. (2015) Human neural stem cell transplantation in ALS: initial results from a phase I trial. J Transl Med 13: 17.
  63. Turner L, Knoepfler P (2016) Selling Stem Cells in the USA: Assessing the Direct-to-Consumer Industry. Cell Stem Cell 19(2): 154-157.
  64. Turner L (2015) US stem cell clinics, patient safety, and the FDA. Trends Mol Med 21(5): 271-273.
  65. Jiang L, Dong BH (2016) Fraudsters operate and officialdom turns a blind eye: a proposal for controlling stem cell therapy in China. Med Health Care Philos 19(3): 403-410.
  66. Kashihara H, Nakayama T, Hatta T, Takahashi N, Fujita M, et al. (2016) Evaluating the quality of website information of private-practice clinics offering cell therapies in Japan. Interact J Med Res 5(2): e15.
  67. Knoepfler PS (2016) When patients reach out, scientists should reach back carefully. Nat med 22(3): 230.
  68. Bonaventura G, Chamayou S, Liprino A, Guglielmino A, Fichera M, et al. (2015) Different tissue-derived stem cells: a comparison of neural differentiation capability. PloS one 10(10): e0140790.
  69. Yan ZJ, Zhang P, Hu YQ, Zhang HT, Hong SQ, et al. (2013) Neural stem-like cells derived from human amnion tissue are effective in treating traumatic brain injury in rat. Neurochem Res 38(5): 1022-1033.
  70. Kopen GC, Prockop DJ, Phinney DG (1999) Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc Natl Acad Sci USA 96(19): 10711-10716.
  71. Peng W, Sun J, Sheng C, Wang Z, Wang Y, et al. (2015) Systematic review and meta-analysis of efficacy of mesenchymal stem cells on locomotor recovery in animal models of traumatic brain injury. Stem Cell Res Ther 6: 47.
  72. Xiong Y, Mahmood A, Chopp M (2010) Neurorestorative treatments for traumatic brain injury. Discov Med 10(54): 434-442.
  73. Zhang Y, Chopp M, Meng Y, Katakowski M, Xin H, et al. (2015) Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury. J Neurosurg 122(4): 856-867.
  74. Haus DL, López Velázquez L, Gold EM, Cunningham KM, Perez H, et al. (2016) Transplantation of human neural stem cells restores cognition in an immunodeficient rodent model of traumatic brain injury. Exp Neurol 281: 1-16.
  75. Tennstaedt A, Aswendt M, Adamczak J, Collienne U, Selt M, et al. (2015) Human neural stem cell intracerebral grafts show spontaneous early neuronal differentiation after several weeks. Biomaterials 44: 143-154.
  76. Hagan M, Wennersten A, Meijer X, Holmin S, Wahlberg L, et al. (2003) Neuroprotection by human neural progenitor cells after experimental contusion in rats. Neurosci Lett 351(3): 149-152.
  77. Gao J, Prough DS, McAdoo DJ, Grady JJ, Parsley MO, et al. (2006) Transplantation of primed human fetal neural stem cells improves cognitive function in rats after traumatic brain injury. Exp Neurol 201(2): 281-292.
  78. Blaya MO, Tsoulfas P, Bramlett HM, Dietrich WD (2015) Neural progenitor cell transplantation promotes neuroprotection, enhances hippocampal neurogenesis, and improves cognitive outcomes after traumatic brain injury. Exp Neurol 264: 67-81.
  79. Ahmed AI, Gajavelli S, Spurlock MS, Chieng LO, Bullock MR (2015) Stem cells for therapy in TBI. J R Army Med Corps 162(2): 98-102.
  80. Harting MT, Sloan LE, Jimenez F, Baumgartner J, Cox CS (2009) Subacute neural stem cell therapy for traumatic brain injury. J Surg Res 153(2): 188-194.
  81. Pendharkar AV, Chua JY, Andres RH, Wang N, Gaeta X, et al. (2010) Biodistribution of neural stem cells after intravascular therapy for hypoxic-ischemia. Stroke 41(9): 2064-2070.
  82. NCT01273337 (2014) Study of ALD-401 Via Intracarotid Infusion in Ischemic Stroke Subjects.
  83. Yavagal DR, Lin B, Raval AP, Garza PS, Dong C (2014) Efficacy and dose-dependent safety of intra-arterial delivery of mesenchymal stem cells in a rodent stroke model. PloS One 9(5): e93735.
  84. Lundberg J, Södersten E, Sundström E, Le Blanc K, Andersson T, et al. (2012) Targeted intra-arterial transplantation of stem cells to the injured CNS is more effective than intravenous administration: engraftment is dependent on cell type and adhesion molecule expression. Cell transplant 21(1): 333-343.
  85. Tajiri N, Acosta SA, Shahaduzzaman M, Ishikawa H, Shinozuka K, et al. (2014) Intravenous transplants of human adipose-derived stem cell protect the brain from traumatic brain injury-induced neurodegeneration and motor and cognitive impairments: cell graft biodistribution and soluble factors in young and aged rats. J Neurosci 34(1): 313-326.
  86. Hyun I, Lindvall O, Ahrlund Richter L, Cattaneo E, Cavazzana Calvo M, et al. (2008) New ISSCR guidelines underscore major principles for responsible translational stem cell research. Cell Stem Cell 3(6): 607-609.
  87. Daley GQ, Hyun I, Apperley JF, Barker RA, Benvenisty N, et al. (2016) Setting global standards for stem cell research and clinical translation: The 2016 ISSCR Guidelines. Stem cell reports 6(6): 787-797.
  88. Kimmelman J, Heslop HE, Sugarman J, Studer L, Benvenisty N, et al. (2016) New ISSCR guidelines: clinical translation of stem cell research. Lancet 387(10032): 1979-1981.
  89. Kimmelman J, Hyun I, Benvenisty N, Caulfield T, Heslop HE, et al. (2016) Policy: Global standards for stem-cell research. Nature 533(7603): 311-313.
© 2014-2018 MedCrave Group, All rights reserved. No part of this content may be reproduced or transmitted in any form or by any means as per the standard guidelines of fair use.
Creative Commons License Open Access by MedCrave Group is licensed under a Creative Commons Attribution 4.0 International License.
Based on a work at
Best viewed in Mozilla Firefox | Google Chrome | Above IE 7.0 version | Opera |Privacy Policy