Next Article in Journal
Recent Insights into the Control of Human Papillomavirus (HPV) Genome Stability, Loss, and Degradation
Next Article in Special Issue
Myogenic Precursors from iPS Cells for Skeletal Muscle Cell Replacement Therapy
Previous Article in Journal
NLRP3 Inflammasome and Pathobiology in AMD
Previous Article in Special Issue
Design of a Tumorigenicity Test for Induced Pluripotent Stem Cell (iPSC)-Derived Cell Products
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

The State of Play with iPSCs and Spinal Cord Injury Models

School of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, Western Australia 6009, Australia
Control of Pluripotency Laboratory, Department of Physiological Sciences I, Faculty of Medicine, University of Barcelona, Hospital Clinic, Casanova 143, Barcelona 08036, Spain
Faculty of Medicine, The University of Sydney Medical School, Division of Pediatrics and Child Health, Westmead Children's Hospital, Sydney 2010, Australia
School of Anatomy, Physiology and Human Biology, and the Harry Perkins Institute for Medical Research (CCTRM), The University of Western Australia, Western Australia 6009, Australia
Author to whom correspondence should be addressed.
J. Clin. Med. 2015, 4(1), 193-203;
Submission received: 8 October 2014 / Accepted: 8 December 2014 / Published: 14 January 2015
(This article belongs to the Special Issue iPS Cells for Modelling and Treatment of Human Diseases)


The application of induced pluripotent stem cell (iPSC) technologies in cell based strategies, for the repair of the central nervous system (with particular focus on the spinal cord), is moving towards the potential use of clinical grade donor cells. The ability of iPSCs to generate donor neuronal, glial and astrocytic phenotypes for transplantation is highlighted here, and we review recent research using iPSCs in attempts to treat spinal cord injury in various animal models. Also discussed are issues relating to the production of clinical grade iPSCs, recent advances in transdifferentiation protocols for iPSC-derived donor cell populations, concerns about tumourogenicity, and whether iPSC technologies offer any advantages over previous donor cell candidates or tissues already in use as therapeutic tools in experimental spinal cord injury studies.

1. Introduction

Spinal cord injury (SCI) is characterised by damage to sensory and motor function, the extent of any functional loss dependent on the location, extent (severity) and type of injury (contusion vs. transection, incomplete vs. complete). Sensorimotor loss that results from a primary mechanical injury is a result of many interacting pathological factors, including: axonal damage, loss of neurons, activation of astrocytes and microglia, degeneration of oligodendrocytes, and demyelination [1]. The extent of this initial damage is significantly increased by ensuing secondary cascades of ischaemia, anoxia, generation of damaging free-radicals, lipid peroxidation, excitotoxicity, and immune-mediated and inflammatory events (e.g., cytokines), which can stimulate further cell death and tissue loss. A region of spreading degeneration rostral and caudal to the injury site, together with inhibitor molecule production, eventually leads to cavitation as well as a glial scar rich in, among other things, various types of chondroitin sulphate proteoglycans (CSPG) that are extremely inhibitory to axonal regrowth. Strategies to induce repair and promote functional (locomotor) recovery generally aim to reduce the extent of secondary damage and demyelination, promote the re-myelination of damaged (but still viable) axons, induce axonal repair and/or regeneration, and perhaps stimulate an endogenous stem cell response. For decades, extensive research has been conducted into clinically relevant cell transplantation strategies to either promote regeneration or to replace damaged/missing cell populations using: fibroblasts, peripheral nerve grafts and Schwann cell bridges, olfactory ensheathing glia (OEG), embryonic stem cells (ESCs), oligodendroglial progenitor cells (OPCs), adult neural precursor cells (NPCs) and neural stem cells (NSCs), autologous macrophages and mesenchymal precursor cells (MPCs) isolated from bone marrow stroma (BMSCs) (for reviews see [2,3,4,5]). More recently, the possibility of developing strategies that use induced Pluripotent Stem Cell (iPSC) technology to generate donor cell populations has gathered momentum.

2. iPSCs as Neuronal and Glial Candidate Donor Populations

To date, iPSCs have been directed to generate neural crest cells [6,7], peripheral sensory neurons [8], neural stem cells and their neuronal progenitors including specific neuronal subtypes such as dopaminergic neurons [9,10,11,12,13,14,15,16,17] glutamatergic neurons [18,19,20,21], GABAergic neurons [18,19,22], motor neurons [23,24,25,26,27,28,29] (see also Faravelli et al. 2014 for review of methodologies of induction into motor neurons [30]), retinal neurons [31,32,33,34], as well as astrocytes [35,36,37,38] and oligodendrocyte lineages [37,39,40,41,42,43]. iPSCs and their derivatives have been tested in various in vivo animal models of neurological/neurodegenerative disorders including Parkinson’s Disease [9,10,11,12,14,44], demyelination [37,39,40,41,42,43], retinal regeneration [32,33], stroke [45,46,47,48] and peripheral nerve regeneration [7] as well as others (see [49,50]). These studies provide proof-of-principle that iPSCs can be successfully differentiated in vitro to yield a desired progeny that, if necessary, can be effectively subjected to ex vivo gene therapy [51,52] and then transplanted with similar outcomes to other pluripotent ESC therapies [53,54,55,56].

3. iPSCs in Spinal Cord Injury

Despite a rapid increase in iPSC-based studies in recent years, currently there is only a small number of published preclinical studies describing the in vivo use of iPSCs in mouse [57,58,59], rat [36,50,57,58,59,60,61,62] or simian [37,60,61,62] models of SCI, or sub-dural parenchymal injections into non-injured rats [63].
Of these studies, rodent moderate contusion injuries were almost all made at the thoracic level (T9–T10) using the Infinite Horizon Impactor device (delivering 60–70 kDyne forces for mice and 200 kDyne force for rat). An exception was a study that used C4 contusions using the Ohio State Injury Device [61], and Lu et al. [60] recently used C5 lateral hemisections in rats. Simian contusions have to date been more severe (17 g 50 mm drop at C5 using the NYU impactor [37] or a 50 g 10 mm drop at T9 [62]). All published studies using contusive SCI (apart from [62]) have reported neuronal, glial and astrocytic marker expression within or near the lesion after transplantation, with two groups reporting differentiation of donor cells into at least one or all these various cell types [37,50,58,59,60,61,62,63]. These studies used iPSC donor cells that were pre-differentiated into either neurospheres (NS) [58,59], neural precursor cells (NPCs) [61,63], neural stem cells (NSCs) [60,61,62] astrocytes [36] or undifferentiated iPSCs [50]. Sareen et al. [63] found that NPCs derived from iPSCs showed variability in differentiation phenotype and survival characteristics following transplantation, but migrated and integrated within the uninjured cord. Superparamagnetic iron oxide labelled iPSC-derived NSCs were tracked non-invasively using magnetic resonance imaging (MRI) from the cell injection sites in monkeys that extended progressively to the lesion regions [62]. Transplanted iPSC-derived NPCs after early chronic cervical SCI were shown to form neurons, astrocytes and oligodendrocytes at 8 weeks post transplantation, however importantly failed to promote functional recovery in forelimb behavioural tasks.
Whilst murine SCI studies using iPSC-derived donor cells showed functional improvements, others have reported no significant differences in morphological or functional outcomes in another acute moderate contusion SCI model in rats [36,50,60]. Lu et al. [60] reported that 3 months after transplantation, surviving human iPSC-derived NSCs from an 86 year old donor male exhibited extraordinarily long distance axonal growth with the host rat spinal cord, with human axons growing rostral and caudal to the lesion site and forming synaptic structures with host neurons and dendrites. Such extensive growth of immature human cells within the rodent central nervous system (CNS) is similar to that obtained many years ago using grafts of human fetal tissue and neuroblasts (e.g., [64]). In the iPSC study, host axons grew into the donor grafts and also formed synaptic structures, again similar to previous work that used donor fetal material of some kind (e.g., [65]). Taken together the new iPSC work confirms that even in the injured adult CNS it is possible, in some cases, to overcome the inhibitory environment of the lesion and elicit substantial regenerative growth and circuit construction. The grafting technique used by Lu et al. 2014 [60] involved a cocktail of growth factors (including brain-derived neurotrophic factor, neurotrophin-3, platelet-derived growth factor-AA, insulin-like growth factor-1, epidermal growth factor, basic fibroblast growth factor, acidic fibroblast growth factor, glial cell line-derived neurotrophic factor, hepatocyte growth factor, and calpain inhibitor in a fibrin matrix) that previously was shown by the same group to promote robust engraftment of donor (non-iPSC derived) NSCs, extensive integration with host tissue, long-distance outgrowth of axons from grafts and extensive ingrowth of host axons into the graft after acute thoracic (T3) SCI [66].
Significant functional improvement was reported in the initial NSC study [66]; however more recently, Lu et al. (2014) in a C5 lateral hemisection study [60], reported no measurable improvement in forelimb function in host rats despite the use of the same growth cocktail, extensive axonal outgrowth and cellular integration. The authors suggest that the injury type itself, the rate of maturation of donor cells (so that insufficient numbers of mature neurons were present to support recovery), inadequate myelination, undesirable ectopic projections and/or insufficient expression of neurotransmitters could account for the discrepancy between the functional recovery observed between the two studies. Whilst the extent of hindlimb versus forelimb recovery may vary depending on the type and complexity of restored or adapted neural circuitry [60], it is also important to note that independent researchers that attempted to replicate this study (as part of the NIH “Facilities of Research Excellence-Spinal Cord Injury” project to support independent replication) revealed conflicting data relating to ingrowth of host axons into the grafts and behavioural outcomes [67]. Overall, these are very important and influential studies, but the extent to which reported differences also reflect, for example, variation in surgical procedures, the individual contributions of factors in the growth cocktail [68], or differences in the nature and response of the donor cell type after transplantation, needs to be established, and future work should yield valuable information in this regard.
The approach of using restricted or individual populations of donor cells in the hope of achieving regrowth or repair leading to morphological improvements and functional restoration has some limitations. The ability of a wide variety of adult somatic (e.g., Schwann cells, olfactory ensheathing glia) and precursor/progenitor (e.g., NPCs, NSCs, OPCs, MPCs) cells to undergo directed differentiation and perform functionally and phenotypically as required in vitro has not always been reproduced when cells are transplanted into the inhibitory environment of the injured spinal cord in vivo. Perhaps these well characterised donor cells that meet necessary research requirements in a wide variety of controlled settings other than the injured spinal cord, simply fail to “perform” in animal models in vivo because of the antagonistic, often inflammatory environment they find themselves in after transplantation [69]. Those donor cells that eventually survive the host immune response may be unable to successfully respond to the new and dynamic myriad of both inhibitory and growth promoting stimuli of the host’s injured spinal cord that is known to occur in a temporal and spatial fashion after trauma. Simply, the “correct language” that equipped the donor cells with the ability to perform all of those functions observed under controlled conditions in vitro, is no longer able to be understood or followed in vivo. Perhaps by using combined populations of adult stem cell-derived oligodendrocyte, astrocyte and neuronal precursor cells in the same relative proportions as those found within the uninjured (normal) spinal cord, we may achieve a phenotypic state that will allow enhanced plasticity and optimal repair/regrowth.
It is crucial to ensure that appropriate cell controls are used in preclinical SCI studies to evaluate the extent of contribution of different cell phenotypes to the morphological and functional outcomes observed after treatment. This applies to any small populations of incompletely reprogrammed donor cells and/or incompletely pre-differentiated donor iPSCs. Whilst the studies mentioned may suggest that improved outcomes were observed in mouse but not necessarily in rat models of SCI, the disparity in overall results from these very limited number of studies suggest that iPSC-based therapy in SCI warrants more extensive and thorough testing. Ideally, research in this area should be conducted using clinically relevant injury regimes in at least mouse and rat models as outlined in the recommendations and guidelines developed by the International Campaign for Cures of Spinal Cord Injury Paralysis (ICCP) [70] (see also [71,72]). Experimental studies in larger species (e.g., cats and primates) with an ascending and descending tract configuration more similar to the human [73], and capable of more complex sensorimotor behaviors, should also be undertaken. In addition, it may be important to include more relevant control donor cell types, such as cells that have been freeze-thawed.

4. Conclusions

There is a clear need to develop a gold standard positive control for use of stem cells in animal models of SCI, to determine the validity and reliability for future clinical application. It is most likely that stem cell therapy alone will not work for SCI, but will require new efforts to combine stem cell therapy with other treatments perhaps, such as bio-scaffolds, immune response modifications, and the timing of the use of different treatments, although the consensus at present is “the earlier the better”. The threat of tumorigenicity remains to be fully addressed. In SCI studies that used iPSC-derived donor cells, “unsafe” murine iPSC-derived donor cells, but not “safe” donor cells, produced teratomas [59], although another study did not report such teratoma formation [36]. Of those studies using human iPSC-derived donor cells, one study did not report on teratoma formation [57], whilst others reported no evidence of tumour formation [37,50,58,60,61,62,63]. For clinical applications, donor cells must be grown in animal cell-free and serum-free conditions and derivation of the first hESC line with these properties has been a major advance for clinical applications of stem cell therapy [74]. Despite their highly similar expression of genes related to pluripotency and development, there is evidence that iPSCs may occupy a distinct pluripotent “state” from ESCs [50,75], and therefore iPSCs may not have the same capacity as ESCs to generate the whole spectrum of region-specific neural progenitors and functional neuronal subtypes for SCI therapies (and other CNS disorders). Nevertheless, the approaching capacity to produce clinical grade iPSCs, together with advances in the efficiency of transdifferentiation protocols for iPSCs into the required phenotypes, marks a potential focus toward the use of iPSC-derived donor cell populations for cell based therapies. If hESC-derived OPCs can be used in SCI trials (Geron), this should surely herald the addition of the clinical grade iPSCs to the potential repertoire of donor cell candidates for SCI and other neurotrauma related therapies, as long as they are conducted in accordance with Good Clinical Practise (GCP) and the associated regulatory directives.

Author Contributions

All authors contributed intellectually to the contents of this commentary.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Hodgetts, S.; Plant, G.W.; Harvey, A. Spinal cord injury: Experimental animal models and relation to human therapy. In The Spinal Cord: A Christopher and Dana Reeve Foundation Text and Atlas; Watson, C., Paxinos, G., Kayalioglu, G., Heise, C., Eds.; Elsevier: London, UK, 2009; pp. 223–251. [Google Scholar]
  2. Sahni, V.; Kessler, J.A. Stem cell therapies for spinal cord injury. Nat. Rev. Neurol. 2010, 6, 363–372. [Google Scholar] [CrossRef] [PubMed]
  3. Tetzlaff, W. Essentials of Spinal Cord Injury: Basic Research to Clinical Practice, 1st ed.; Fehlings, M.G., Vaccaro, A.R., Boakye, M., Eds.; Thieme: Leipzig, Germany, 2013; pp. 399–420. [Google Scholar]
  4. Tetzlaff, W.; Okon, E.B.; Karimi-Abdolrezaee, S.; Hill, C.E.; Sparling, J.S.; Plemel, J.R.; Plunet, W.T.; Tsai, E.C.; Baptiste, D.; Smithson, L.J.; et al. A systematic review of cellular transplantation therapies for spinal cord injury. J. Neurotrauma 2011, 28, 1611–1682. [Google Scholar] [CrossRef]
  5. Volarevic, V.; Erceg, S.; Bhattacharya, S.S.; Stojkovic, P.; Horner, P.; Stojkovic, M. Stem cell-based therapy for spinal cord injury. Cell Transplant. 2013, 22, 1309–1323. [Google Scholar] [CrossRef] [PubMed]
  6. Lee, G.; Chambers, S.M.; Tomishima, M.J.; Studer, L. Derivation of neural crest cells from human pluripotent stem cells. Nat. Protoc. 2010, 5, 688–701. [Google Scholar] [CrossRef] [PubMed]
  7. Wang, A.; Tang, Z.; Park, I.H.; Zhu, Y.; Patel, S.; Daley, G.Q.; Li, S. Induced pluripotent stem cells for neural tissue engineering. Biomaterials 2011, 32, 5023–5032. [Google Scholar] [CrossRef] [PubMed]
  8. Kitazawa, A.; Shimizu, N. Differentiation of mouse induced pluripotent stem cells into neurons using conditioned medium of dorsal root ganglia. N. Biotechnol. 2011, 28, 326–333. [Google Scholar] [CrossRef] [PubMed]
  9. Wernig, M.; Zhao, J.P.; Pruszak, J.; Hedlund, E.; Fu, D.; Soldner, F.; Broccoli, V.; Constantine-Paton, M.; Isacson, O.; Jaenisch, R. Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with parkinson’s disease. Proc. Natl. Acad. Sci. USA 2008, 105, 5856–5861. [Google Scholar] [CrossRef] [PubMed]
  10. Cai, J.; Yang, M.; Poremsky, E.; Kidd, S.; Schneider, J.S.; Iacovitti, L. Dopaminergic neurons derived from human induced pluripotent stem cells survive and integrate into 6-OHDA-lesioned rats. Stem Cells Dev. 2010, 19, 1017–1023. [Google Scholar] [CrossRef] [PubMed]
  11. Deleidi, M.; Hargus, G.; Hallett, P.; Osborn, T.; Isacson, O. Development of histocompatible primate-induced pluripotent stem cells for neural transplantation. Stem Cells 2011, 29, 1052–1063. [Google Scholar] [CrossRef] [PubMed]
  12. Rhee, Y.H.; Ko, J.Y.; Chang, M.Y.; Yi, S.H.; Kim, D.; Kim, C.H.; Shim, J.W.; Jo, A.Y.; Kim, B.W.; Lee, H.; et al. Protein-based human iPS cells efficiently generate functional dopamine neurons and can treat a rat model of parkinson disease. J. Clin. Invest. 2011, 121, 2326–2335. [Google Scholar] [CrossRef] [PubMed]
  13. Swistowski, A.; Peng, J.; Liu, Q.; Mali, P.; Rao, M.S.; Cheng, L.; Zeng, X. Efficient generation of functional dopaminergic neurons from human induced pluripotent stem cells under defined conditions. Stem Cells 2010, 28, 1893–1904. [Google Scholar] [CrossRef] [PubMed]
  14. Sanchez-Danes, A.; Consiglio, A.; Richaud, Y.; Rodriguez-Piza, I.; Dehay, B.; Edel, M.; Bove, J.; Memo, M.; Vila, M.; Raya, A.; et al. Efficient generation of A9 midbrain dopaminergic neurons by lentiviral delivery of LMX1A in human embryonic stem cells and induced pluripotent stem cells. Hum. Gene Ther. 2012, 23, 56–69. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Pfisterer, U.; Kirkeby, A.; Torper, O.; Wood, J.; Nelander, J.; Dufour, A.; Bjorklund, A.; Lindvall, O.; Jakobsson, J.; Parmar, M. Direct conversion of human fibroblasts to dopaminergic neurons. Proc. Natl. Acad. Sci. USA 2011, 108, 10343–10348. [Google Scholar] [CrossRef] [PubMed]
  16. Pfisterer, U.; Wood, J.; Nihlberg, K.; Hallgren, O.; Bjermer, L.; Westergren-Thorsson, G.; Lindvall, O.; Parmar, M. Efficient induction of functional neurons from adult human fibroblasts. Cell Cycle 2011, 10, 3311–3316. [Google Scholar] [CrossRef] [PubMed]
  17. Caiazzo, M.; Dell’Anno, M.T.; Dvoretskova, E.; Lazarevic, D.; Taverna, S.; Leo, D.; Sotnikova, T.D.; Menegon, A.; Roncaglia, P.; Colciago, G.; et al. Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 2011, 476, 224–227. [Google Scholar] [CrossRef]
  18. Kim, J.E.; O’Sullivan, M.L.; Sanchez, C.A.; Hwang, M.; Israel, M.A.; Brennand, K.; Deerinck, T.J.; Goldstein, L.S.; Gage, F.H.; Ellisman, M.H.; et al. Investigating synapse formation and function using human pluripotent stem cell-derived neurons. Proc. Natl. Acad. Sci. USA 2011, 108, 3005–3010. [Google Scholar] [CrossRef] [PubMed]
  19. Marchetto, M.C.; Carromeu, C.; Acab, A.; Yu, D.; Yeo, G.W.; Mu, Y.; Chen, G.; Gage, F.H.; Muotri, A.R. A model for neural development and treatment of rett syndrome using human induced pluripotent stem cells. Cell 2010, 143, 527–539. [Google Scholar] [CrossRef] [PubMed]
  20. Pedrosa, E.; Sandler, V.; Shah, A.; Carroll, R.; Chang, C.; Rockowitz, S.; Guo, X.; Zheng, D.; Lachman, H.M. Development of patient-specific neurons in schizophrenia using induced pluripotent stem cells. J. Neurogenet. 2011, 25, 88–103. [Google Scholar] [CrossRef] [PubMed]
  21. Zeng, H.; Guo, M.; Martins-Taylor, K.; Wang, X.; Zhang, Z.; Park, J.W.; Zhan, S.; Kronenberg, M.S.; Lichtler, A.; Liu, H.X.; et al. Specification of region-specific neurons including forebrain glutamatergic neurons from human induced pluripotent stem cells. PLoS One 2010, 5, e11853. [Google Scholar] [CrossRef] [PubMed]
  22. Brennand, K.J.; Simone, A.; Jou, J.; Gelboin-Burkhart, C.; Tran, N.; Sangar, S.; Li, Y.; Mu, Y.; Chen, G.; Yu, D.; et al. Modelling schizophrenia using human induced pluripotent stem cells. Nature 2011, 473, 221–225. [Google Scholar] [CrossRef] [PubMed]
  23. Boulting, G.L.; Kiskinis, E.; Croft, G.F.; Amoroso, M.W.; Oakley, D.H.; Wainger, B.J.; Williams, D.J.; Kahler, D.J.; Yamaki, M.; Davidow, L.; et al. A functionally characterized test set of human induced pluripotent stem cells. Nat. Biotechnol. 2011, 29, 279–286. [Google Scholar] [CrossRef] [PubMed]
  24. Hester, M.E.; Murtha, M.J.; Song, S.; Rao, M.; Miranda, C.J.; Meyer, K.; Tian, J.; Boulting, G.; Schaffer, D.V.; Zhu, M.X.; et al. Rapid and efficient generation of functional motor neurons from human pluripotent stem cells using gene delivered transcription factor codes. Mol. Ther. 2011, 19, 1905–1912. [Google Scholar] [CrossRef] [PubMed]
  25. Hu, B.Y.; Weick, J.P.; Yu, J.; Ma, L.X.; Zhang, X.Q.; Thomson, J.A.; Zhang, S.C. Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency. Proc. Natl. Acad. Sci. USA 2010, 107, 4335–4340. [Google Scholar] [CrossRef] [PubMed]
  26. Karumbayaram, S.; Novitch, B.G.; Patterson, M.; Umbach, J.A.; Richter, L.; Lindgren, A.; Conway, A.E.; Clark, A.T.; Goldman, S.A.; Plath, K.; et al. Directed differentiation of human-induced pluripotent stem cells generates active motor neurons. Stem Cells 2009, 27, 806–811. [Google Scholar] [CrossRef] [PubMed]
  27. Amoroso, M.W.; Croft, G.F.; Williams, D.J.; O’Keeffe, S.; Carrasco, M.A.; Davis, A.R.; Roybon, L.; Oakley, D.H.; Maniatis, T.; Henderson, C.E.; et al. Accelerated high-yield generation of limb-innervating motor neurons from human stem cells. J. Neurosci. 2013, 33, 574–586. [Google Scholar] [CrossRef] [PubMed]
  28. Burkard, T.; Kaiser, C.A.; Brunner-La Rocca, H.; Osswald, S.; Pfisterer, M.E.; Jeger, R.V.; Investigators, B. Combined clopidogrel and proton pump inhibitor therapy is associated with higher cardiovascular event rates after percutaneous coronary intervention: A report from the basket trial. J. Int. Med. 2012, 271, 257–263. [Google Scholar] [CrossRef]
  29. Sareen, D.; O’Rourke, J.G.; Meera, P.; Muhammad, A.K.; Grant, S.; Simpkinson, M.; Bell, S.; Carmona, S.; Ornelas, L.; Sahabian, A.; et al. Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion. Sci. Transl. Med. 2013, 5. [Google Scholar] [CrossRef]
  30. Faravelli, I.; Bucchia, M.; Rinchetti, P.; Nizzardo, M.; Simone, C.; Frattini, E.; Corti, S. Motor neuron derivation from human embryonic and induced pluripotent stem cells: Experimental approaches and clinical perspectives. Stem Cell Res. Ther. 2014, 5. [Google Scholar] [CrossRef]
  31. Hirami, Y.; Osakada, F.; Takahashi, K.; Okita, K.; Yamanaka, S.; Ikeda, H.; Yoshimura, N.; Takahashi, M. Generation of retinal cells from mouse and human induced pluripotent stem cells. Neurosci. Lett. 2009, 458, 126–131. [Google Scholar] [CrossRef] [PubMed]
  32. Parameswaran, S.; Balasubramanian, S.; Babai, N.; Qiu, F.; Eudy, J.D.; Thoreson, W.B.; Ahmad, I. Induced pluripotent stem cells generate both retinal ganglion cells and photoreceptors: Therapeutic implications in degenerative changes in glaucoma and age-related macular degeneration. Stem Cells 2010, 28, 695–703. [Google Scholar] [CrossRef] [PubMed]
  33. Tucker, B.A.; Park, I.H.; Qi, S.D.; Klassen, H.J.; Jiang, C.; Yao, J.; Redenti, S.; Daley, G.Q.; Young, M.J. Transplantation of adult mouse iPS cell-derived photoreceptor precursors restores retinal structure and function in degenerative mice. PLoS One 2011, 6, e18992. [Google Scholar] [CrossRef] [PubMed]
  34. Zhou, L.; Wang, W.; Liu, Y.; Fernandez de Castro, J.; Ezashi, T.; Telugu, B.P.; Roberts, R.M.; Kaplan, H.J.; Dean, D.C. Differentiation of induced pluripotent stem cells of swine into ROD photoreceptors and their integration into the retina. Stem Cells 2011, 29, 972–980. [Google Scholar] [CrossRef] [PubMed]
  35. Emdad, L.; D’Souza, S.L.; Kothari, H.P.; Qadeer, Z.A.; Germano, I.M. Efficient differentiation of human embryonic and induced pluripotent stem cells into functional astrocytes. Stem Cells Dev. 2012, 21, 404–410. [Google Scholar] [CrossRef] [PubMed]
  36. Hayashi, K.; Hashimoto, M.; Koda, M.; Naito, A.T.; Murata, A.; Okawa, A.; Takahashi, K.; Yamazaki, M. Increase of sensitivity to mechanical stimulus after transplantation of murine induced pluripotent stem cell-derived astrocytes in a rat spinal cord injury model. J. Neurosurg. Spine 2011, 15, 582–593. [Google Scholar] [CrossRef] [PubMed]
  37. Kobayashi, Y.; Okada, Y.; Itakura, G.; Iwai, H.; Nishimura, S.; Yasuda, A.; Nori, S.; Hikishima, K.; Konomi, T.; Fujiyoshi, K.; et al. Pre-evaluated safe human iPSC-derived neural stem cells promote functional recovery after spinal cord injury in common marmoset without tumorigenicity. PLoS One 2012, 7, e52787. [Google Scholar] [CrossRef]
  38. Krencik, R.; Weick, J.P.; Liu, Y.; Zhang, Z.J.; Zhang, S.C. Specification of transplantable astroglial subtypes from human pluripotent stem cells. Nat. Biotechnol. 2011, 29, 528–534. [Google Scholar] [CrossRef] [PubMed]
  39. Czepiel, M.; Balasubramaniyan, V.; Schaafsma, W.; Stancic, M.; Mikkers, H.; Huisman, C.; Boddeke, E.; Copray, S. Differentiation of induced pluripotent stem cells into functional oligodendrocytes. Glia 2011, 59, 882–892. [Google Scholar] [CrossRef] [PubMed]
  40. Ogawa, S.; Tokumoto, Y.; Miyake, J.; Nagamune, T. Induction of oligodendrocyte differentiation from adult human fibroblast-derived induced pluripotent stem cells. In Vitro Cell Dev. Biol. Anim. 2011, 47, 464–469. [Google Scholar] [CrossRef] [PubMed]
  41. Ogawa, S.; Tokumoto, Y.; Miyake, J.; Nagamune, T. Immunopanning selection of A2B5-positive cells increased the differentiation efficiency of induced pluripotent stem cells into oligodendrocytes. Neurosci. Lett. 2011, 489, 79–83. [Google Scholar] [CrossRef] [PubMed]
  42. Pouya, A.; Satarian, L.; Kiani, S.; Javan, M.; Baharvand, H. Human induced pluripotent stem cells differentiation into oligodendrocyte progenitors and transplantation in a rat model of optic chiasm demyelination. PLoS One 2011, 6, e27925. [Google Scholar] [PubMed]
  43. Tokumoto, Y.; Ogawa, S.; Nagamune, T.; Miyake, J. Comparison of efficiency of terminal differentiation of oligodendrocytes from induced pluripotent stem cells versus embryonic stem cells in vitro. J. Biosci. Bioeng. 2010, 109, 622–628. [Google Scholar] [CrossRef] [PubMed]
  44. Hargus, G.; Cooper, O.; Deleidi, M.; Levy, A.; Lee, K.; Marlow, E.; Yow, A.; Soldner, F.; Hockemeyer, D.; Hallett, P.J.; et al. Differentiated parkinson patient-derived induced pluripotent stem cells grow in the adult rodent brain and reduce motor asymmetry in parkinsonian rats. Proc. Natl. Acad. Sci. USA 2010, 107, 15921–15926. [Google Scholar] [CrossRef] [PubMed]
  45. Chen, A.; Xu, X.M.; Kleitman, N.; Bunge, M.B. Methylprednisolone administration improves axonal regeneration into schwann cell grafts in transected adult rat thoracic spinal cord. Exp. Neurol. 1996, 138, 261–276. [Google Scholar] [CrossRef] [PubMed]
  46. Chen, S.J.; Chang, C.M.; Tsai, S.K.; Chang, Y.L.; Chou, S.J.; Huang, S.S.; Tai, L.K.; Chen, Y.C.; Ku, H.H.; Li, H.Y.; et al. Functional improvement of focal cerebral ischemia injury by subdural transplantation of induced pluripotent stem cells with fibrin glue. Stem Cells Dev. 2010, 19, 1757–1767. [Google Scholar] [CrossRef] [PubMed]
  47. Jiang, M.; Lv, L.; Ji, H.; Yang, X.; Zhu, W.; Cai, L.; Gu, X.; Chai, C.; Huang, S.; Sun, J.; et al. Induction of pluripotent stem cells transplantation therapy for ischemic stroke. Mol. Cell. Biochem. 2011, 354, 67–75. [Google Scholar] [CrossRef] [PubMed]
  48. Yamashita, T.; Kawai, H.; Tian, F.; Ohta, Y.; Abe, K. Tumorigenic development of induced pluripotent stem cells in ischemic mouse brain. Cell Transplant. 2011, 20, 883–891. [Google Scholar] [CrossRef] [PubMed]
  49. Saporta, M.A.; Grskovic, M.; Dimos, J.T. Induced pluripotent stem cells in the study of neurological diseases. Stem Cell Res. Ther. 2011, 2, 37. [Google Scholar] [CrossRef] [PubMed]
  50. Kramer, A.S.; Plant, G.W.; Harvey, A.R.; Hodgetts, S.I. Systematic review of induced pluripotent stem cell technology as a potential clinical therapy for spinal cord injury. Cell Transplant. 2012, 22, 571–617. [Google Scholar] [CrossRef] [PubMed]
  51. Hanna, J.; Wernig, M.; Markoulaki, S.; Sun, C.W.; Meissner, A.; Cassady, J.P.; Beard, C.; Brambrink, T.; Wu, L.C.; Townes, T.M.; et al. Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 2007, 318, 1920–1923. [Google Scholar] [CrossRef] [PubMed]
  52. Xu, D.; Alipio, Z.; Fink, L.M.; Adcock, D.M.; Yang, J.; Ward, D.C.; Ma, Y. Phenotypic correction of murine hemophilia a using an iPS cell-based therapy. Proc. Natl. Acad. Sci. USA 2009, 106, 808–813. [Google Scholar] [CrossRef] [PubMed]
  53. Chin, M.H.; Mason, M.J.; Xie, W.; Volinia, S.; Singer, M.; Peterson, C.; Ambartsumyan, G.; Aimiuwu, O.; Richter, L.; Zhang, J.; et al. Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures. Cell Stem Cell 2009, 5, 111–123. [Google Scholar] [CrossRef] [PubMed]
  54. Chin, M.H.; Pellegrini, M.; Plath, K.; Lowry, W.E. Molecular analyses of human induced pluripotent stem cells and embryonic stem cells. Cell Stem Cell 2010, 7, 263–269. [Google Scholar] [CrossRef] [PubMed]
  55. Guenther, M.G.; Frampton, G.M.; Soldner, F.; Hockemeyer, D.; Mitalipova, M.; Jaenisch, R.; Young, R.A. Chromatin structure and gene expression programs of human embryonic and induced pluripotent stem cells. Cell Stem Cell 2010, 7, 249–257. [Google Scholar] [CrossRef] [PubMed]
  56. Newman, A.M.; Cooper, J.B. Lab-specific gene expression signatures in pluripotent stem cells. Cell Stem Cell 2010, 7, 258–262. [Google Scholar] [CrossRef] [PubMed]
  57. Fujimoto, Y.; Abematsu, M.; Falk, A.; Tsujimura, K.; Sanosaka, T.; Juliandi, B.; Semi, K.; Namihira, M.; Komiya, S.; Smith, A.; et al. Treatment of a mouse model of spinal cord injury by transplantation of human induced pluripotent stem cell-derived long-term self-renewing neuroepithelial-like stem cells. Stem Cells 2012, 30, 1163–1173. [Google Scholar] [CrossRef] [PubMed]
  58. Nori, S.; Okada, Y.; Yasuda, A.; Tsuji, O.; Takahashi, Y.; Kobayashi, Y.; Fujiyoshi, K.; Koike, M.; Uchiyama, Y.; Ikeda, E.; et al. Grafted human-induced pluripotent stem-cell-derived neurospheres promote motor functional recovery after spinal cord injury in mice. Proc. Natl. Acad. Sci. USA 2011, 108, 16825–16830. [Google Scholar] [CrossRef] [PubMed]
  59. Tsuji, O.; Miura, K.; Okada, Y.; Fujiyoshi, K.; Mukaino, M.; Nagoshi, N.; Kitamura, K.; Kumagai, G.; Nishino, M.; Tomisato, S.; et al. Therapeutic potential of appropriately evaluated safe-induced pluripotent stem cells for spinal cord injury. Proc. Natl. Acad. Sci. USA 2010, 107, 12704–12709. [Google Scholar] [CrossRef] [PubMed]
  60. Lu, P.; Woodruff, G.; Wang, Y.; Graham, L.; Hunt, M.; Wu, D.; Boehle, E.; Ahmad, R.; Poplawski, G.; Brock, J.; et al. Long-distance axonal growth from human induced pluripotent stem cells after spinal cord injury. Neuron 2014, 83, 789–796. [Google Scholar] [CrossRef] [PubMed]
  61. Nutt, S.E.; Chang, E.A.; Suhr, S.T.; Schlosser, L.O.; Mondello, S.E.; Moritz, C.T.; Cibelli, J.B.; Horner, P.J. Caudalized human iPSC-derived neural progenitor cells produce neurons and glia but fail to restore function in an early chronic spinal cord injury model. Exp. Neurol. 2013, 248, 491–503. [Google Scholar] [CrossRef] [PubMed]
  62. Tang, H.; Sha, H.; Sun, H.; Wu, X.; Xie, L.; Wang, P.; Xu, C.; Larsen, C.; Zhang, H.L.; Gong, Y.; et al. Tracking induced pluripotent stem cells-derived neural stem cells in the central nervous system of rats and monkeys. Cell. Reprogram. 2013, 15, 435–442. [Google Scholar] [CrossRef] [PubMed]
  63. Sareen, D.; Gowing, G.; Sahabian, A.; Staggenborg, K.; Paradis, R.; Avalos, P.; Latter, J.; Ornelas, L.; Garcia, L.; Svendsen, C.N. Human induced pluripotent stem cells are a novel source of neural progenitor cells (iNPCs) that migrate and integrate in the rodent spinal cord. J. Comp. Neurol. 2014, 522, 2707–2728. [Google Scholar] [CrossRef] [PubMed]
  64. Wictorin, K.; Brundin, P.; Gustavii, B.; Lindvall, O.; Bjorklund, A. Reformation of long axon pathways in adult rat central nervous system by human forebrain neuroblasts. Nature 1990, 347, 556–558. [Google Scholar] [CrossRef] [PubMed]
  65. Thompson, L.; Bjorklund, A. Survival, differentiation, and connectivity of ventral mesencephalic dopamine neurons following transplantation. Prog. Brain Res. 2012, 200, 61–95. [Google Scholar] [PubMed]
  66. Lu, P.; Wang, Y.; Graham, L.; McHale, K.; Gao, M.; Wu, D.; Brock, J.; Blesch, A.; Rosenzweig, E.S.; Havton, L.A.; et al. Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell 2012, 150, 1264–1273. [Google Scholar] [CrossRef] [PubMed]
  67. Sharp, K.G.; Flanagan, L.A.; Yee, K.M.; Steward, O. A re-assessment of a combinatorial treatment involving schwann cell transplants and elevation of cyclic AMP on recovery of motor function following thoracic spinal cord injury in rats. Exp. Neurol. 2012, 233, 625–644. [Google Scholar] [CrossRef] [PubMed]
  68. Harvey, A.R.; Lovett, S.J.; Majda, B.T.; Yoon, J.H.; Wheeler, L.P.G.; Hodgetts, S.I. Neurotrophic factors for spinal cord repair: Wwhich, where, how and when to apply, and for what period of time? Brain Res. 2014, in press. [Google Scholar]
  69. Emsley, J.G.; Mitchell, B.D.; Kempermann, G.; Macklis, J.D. Adult neurogenesis and repair of the adult CNS with neural progenitors, precursors, and stem cells. Prog. Neurobiol. 2005, 75, 321–341. [Google Scholar] [CrossRef] [PubMed]
  70. Fawcett, J.W.; Curt, A.; Steeves, J.D.; Coleman, W.P.; Tuszynski, M.H.; Lammertse, D.; Bartlett, P.F.; Blight, A.R.; Dietz, V.; Ditunno, J.; et al. Guidelines for the conduct of clinical trials for spinal cord injury as developed by the iccp panel: Spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials. Spinal Cord 2007, 45, 190–205. [Google Scholar] [CrossRef] [PubMed]
  71. Lemmon, V.P.; Abeyruwan, S.; Visser, U.; Bixby, J.L. Facilitating transparency in spinal cord injury studies using data standards and ontologies. Neural Regen. Res. 2014, 9, 6–7. [Google Scholar] [CrossRef] [PubMed]
  72. Lemmon, V.P.; Ferguson, A.R.; Popovich, P.G.; Xu, X.M.; Snow, D.M.; Igarashi, M.; Beattie, C.E.; Bixby, J.L. Minimum information about a spinal cord injury experiment: A proposed reporting standard for spinal cord injury experiments. J. Neurotrauma 2014, 31, 1354–1361. [Google Scholar] [CrossRef] [PubMed]
  73. Watson, C.R.R.; Harvey, A.R. Projections from the brain to the spinal cord. In The Spinal Cord: A Christopher and Dana Reeve Foundation Text and Atlas; Watson, C., Paxinos, G., Kayalioglu, G., Heise, C., Eds.; Elsevier: London, UK, 2009; pp. 182–193. [Google Scholar]
  74. Klimanskaya, I.; Chung, Y.; Meisner, L.; Johnson, J.; West, M.D.; Lanza, R. Human embryonic stem cells derived without feeder cells. Lancet 2005, 365, 1636–1641. [Google Scholar] [CrossRef] [PubMed]
  75. Lister, R.; Mukamel, E.A.; Nery, J.R.; Urich, M.; Puddifoot, C.A.; Johnson, N.D.; Lucero, J.; Huang, Y.; Dwork, A.J.; Schultz, M.D.; et al. Global epigenomic reconfiguration during mammalian brain development. Science 2013, 341. [Google Scholar] [CrossRef]

Share and Cite

MDPI and ACS Style

Hodgetts, S.I.; Edel, M.; Harvey, A.R. The State of Play with iPSCs and Spinal Cord Injury Models. J. Clin. Med. 2015, 4, 193-203.

AMA Style

Hodgetts SI, Edel M, Harvey AR. The State of Play with iPSCs and Spinal Cord Injury Models. Journal of Clinical Medicine. 2015; 4(1):193-203.

Chicago/Turabian Style

Hodgetts, Stuart I., Michael Edel, and Alan R. Harvey. 2015. "The State of Play with iPSCs and Spinal Cord Injury Models" Journal of Clinical Medicine 4, no. 1: 193-203.

Article Metrics

Back to TopTop