Spinal cord injury (SCI) is a devastating and irreversible event, and much research using fibroblast growth factor-2 (FGF-2) has been performed to test its capacity to blunt the effects of SCI as well as to provide an environment conducive for SCI repair.
We tested how the in vitro release of FGF-2 from heparin-conjugated poly(L-lactide-co-glycolide) (PLGA)-conjugated nanospheres (HCPNs) affected the growth of human bone marrow-derived mesenchymal stem cells (hBMSCs), as well as the effects of their co-transplantation in an animal model of SCI.
Our results showed that sustained, long-term release of FGF-2 from HCPNs significantly increased hBMSCs proliferation in vitro, and that their co-transplantation following rat SCI lead to increased functional improvement, a greater amount of hBMSCs surviving transplantation, and a greater density of neurofilament-positive cells in the injury epicenter.
These results suggest a proliferative, protective, and neural inductive potential of FGF-2 for transplanted hBMSCs, as well as a possible role for sustained FGF-2 delivery along with hBMSCs transplantation in the injured spinal cord. Future studies will be required to ascertain the safety FGF-2-containing HCPNs before clinical application.
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Akiyama Y, Radtke C, Kocsis JD (2002) Remyelination of the rat spinal cord by transplantation of identified bone marrow stromal cells. J Neurosci 22:6623–6630
Basso DM, Beattie MS, Bresnahan JC (1996) Graded histological and locomotor outcomes after spinal cord contusion using the NYU weight-drop device versus transection. Exp Neurol 139:244–256
Chappell JC, Song J, Burke CW, Klibanov AL, Price RJ (2008) Targeted Delivery of Nanoparticles Bearing Fibroblast Growth Factor-2 by Ultrasonic Microbubble Destruction for Therapeutic Arteriogenesis. Small 4:1769–1777
Cizkova D, Rosocha J, Vanicky I, Jergova S, Čížek M (2006) Transplants of Human Mesenchymal Stem Cells Improve Functional Recovery After Spinal Cord Injury in the Rat. Cell Mol Neurobiol 26:1165–1178
Clements BA, Hsu CYM, Kucharski C, Lin X, Rose L, Uludağ H (2009) Nonviral Delivery of Basic Fibroblast Growth Factor Gene to Bone Marrow Stromal Cells. Clin Orthop Relat Res 467:3129–3137
Dasari VR, Spomar DG, Cady C, Gujrati M, Rao JS, Dinh DH (2007) Mesenchymal stem cells from rat bone marrow downregulate caspase-3-mediated apoptotic pathway after spinal cord injury in rats. Neurochem Res 32:2080–2093
Guo Q, Sebastian L, Sopher BL, Miller MW, Glazner GW, Ware CB, Martin GM, Mattson MP (1999) Neurotrophic factors [activity-dependent neurotrophic factor (ADNF) and basic fibroblast growth factor (bFGF)] interrupt excitotoxic neurodegenerative cascades promoted by a PS1 mutation. Proc Natl Acad Sci U S A 96:4125–4130
Hofstetter CP, Schwarz EJ, Hess D, Widenfalk J, El Manira A, Prockop DJ, Olson L (2002) Marrow stromal cells form guiding strands in the injured spinal cord and promote recovery. Proc Natl Acad Sci U S A 99:2199–2204
Iwasaki YSTIKTNKTKM (1995) Acidic and basic fibroblast growth factors enhance neurite outgrowth in cultured rat spinal cord neurons. Neurol Res 17:70–72
Jeon O, Kang S-W, Lim H-W, Hyung Chung J, Kim B-S (2006) Long-term and zero-order release of basic fibroblast growth factor from heparin-conjugated poly(l-lactide-co-glycolide) nanospheres and fibrin gel. Biomaterials 27:1598–1607
Jimenez Hamann MC, Tator CH, Shoichet MS (2005) Injectable intrathecal delivery system for localized administration of EGF and FGF-2 to the injured rat spinal cord. Exp Neurol 194:106–119
Jin K, LaFevre-Bernt M, Sun Y, Chen S, Gafni J, Crippen D, Logvinova A, Ross CA, Greenberg DA, Ellerby LM (2005) FGF-2 promotes neurogenesis and neuroprotection and prolongs survival in a transgenic mouse model of Huntington's disease. Proc Natl Acad Sci U S A 102:18189–18194
Kim K-N, Oh SH, Lee KH, Yoon D-H (2006) Effect of human mesenchymal stem cell transplantation combined with growth factor infusion in the repair of injured spinal cord. Acta Neurochir Suppl 99:133–136
Kuh S-U, Cho Y-E, Yoon D-H, Kim K-N, Ha Y (2005) Functional recovery after human umbilical cord blood cells transplantation with brain-derived neutrophic factor into the spinal cord injured rat. Acta Neurochir 147:985–992, discussion 992
Lee KH, Suh-Kim H, Choi JS, Jeun S-S, Kim EJ, Kim S-S, Yoon DH, Lee BH (2007) Human mesenchymal stem cell transplantation promotes functional recovery following acute spinal cord injury in rats. Acta Neurobiol Exp (Wars) 67:13–22
Lian Jin H, Pennant WA, Hyung Lee M, Su S, Ah Kim H, Lu Liu M, Soo Oh J, Cho J, Nyun Kim K, Heum Yoon D, Ha Y (2011) Neural Stem Cells Modified by a Hypoxia-Inducible VEGF Gene Expression System Improve Cell Viability under Hypoxic Conditions and Spinal Cord Injury. Spine 36:857–864
Liu Z, Li Y, Qu R, Shen L, Gao Q, Zhang X, Lu M, Savant-Bhonsale S, Borneman J, Chopp M (2007) Axonal sprouting into the denervated spinal cord and synaptic and postsynaptic protein expression in the spinal cord after transplantation of bone marrow stromal cell in stroke rats. Brain Res 1149:172–180
Martin I, Muraglia A, Campanile G, Cancedda R, Quarto R (1997) Fibroblast growth factor-2 supports ex vivo expansion and maintenance of osteogenic precursors from human bone marrow. Endocrinology 138:4456–4462
Mattson MP, Kumar KN, Wang H, Cheng B, Michaelis EK (1993) Basic FGF regulates the expression of a functional 71 kDa NMDA receptor protein that mediates calcium influx and neurotoxicity in hippocampal neurons. J Neurosci: Off J Soc Neurosci 13:4575–4588
Meijs MF, Timmers L, Pearse DD, Tresco PA, Bates ML, Joosten EA, Bartlett Bunge M, Oudega M (2004) Basic fibroblast growth factor promotes neuronal survival but not behavioral recovery in the transected and Schwann cell implanted rat thoracic spinal cord. J Neurotrauma 21:1415–1430
Ohori Y, Si Y, Nagao M, Sugimori M, Yamamoto N, Nakamura K, Nakafuku M (2006) Growth Factor Treatment and Genetic Manipulation Stimulate Neurogenesis and Oligodendrogenesis by Endogenous Neural Progenitors in the Injured Adult Spinal Cord. J Neurosci 26:11948–11960
Ohta M (2004) Bone marrow stromal cells infused into the cerebrospinal fluid promote functional recovery of the injured rat spinal cord with reduced cavity formation. Exp Neurol 187:266–278
Pri-Chen S, Pitaru S, Lokiec F, Savion N (1998) Basic fibroblast growth factor enhances the growth and expression of the osteogenic phenotype of dexamethasone-treated human bone marrow-derived bone-like cells in culture. Bone 23:111–117
Rabchevsky AG, Fugaccia I, Turner AF, Blades DA, Mattson MP, Scheff SW (2000) Basic Fibroblast Growth Factor (bFGF) Enhances Functional Recovery Following Severe Spinal Cord Injury to the Rat. Exp Neurol 164:280–291
Shihabuddin LS, Ray J, Gage FH (1997) FGF-2 is sufficient to isolate progenitors found in the adult mammalian spinal cord. Exp Neurol 148:577–586
Shin DA, Kim JM, Kim HI, Yi S, Ha Y, Yoon Do H, Kim KN (2013) Comparison of functional and histological outcomes after intralesional, intracisternal, and intravenous transplantation of human bone marrow-derived mesenchymal stromal cells in a rat model of spinal cord injury. Acta Neurochir 155:1943–1950, Wien
Teng YD, Mocchetti I, Taveira-DaSilva AM, Gillis RA, Wrathall JR (1999) Basic fibroblast growth factor increases long-term survival of spinal motor neurons and improves respiratory function after experimental spinal cord injury. J Neurosci 19:7037–7047
Wu S, Suzuki Y, Ejiri Y, Noda T, Bai H, Kitada M, Kataoka K, Ohta M, Chou H, Ide C (2003) Bone marrow stromal cells enhance differentiation of cocultured neurosphere cells and promote regeneration of injured spinal cord. J Neurosci Res 72:343–351
Yang H, Xia Y, Lu SQ, Soong TW, Feng ZW (2008) Basic fibroblast growth factor-induced neuronal differentiation of mouse bone marrow stromal cells requires FGFR-1, MAPK/ERK, and transcription factor AP-1. J Biol Chem 283:5287–5295
Yoshihara T, Ohta M, Itokazu Y, Matsumoto N, Dezawa M, Suzuki Y, Taguchi A, Watanabe Y, Adachi Y, Ikehara S, Sugimoto H, Ide C (2007) Neuroprotective Effect of Bone Marrow–Derived Mononuclear Cells Promoting Functional Recovery from Spinal Cord Injury. J Neurotrauma 24:1026–1036
1. The Stem Cell Research Center of the 21st Century Frontier Research Program, Ministry of Education, Science and Technology, Korea
2. The Korea Healthcare technology R&D project, Ministry for Health & Welfare Affairs, Republic of Korea (A111016)
Conflicts of interest
Dong Ah Shin and William A. Pennant contributed equally to this work.
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Shin, D.A., Pennant, W.A., Yoon, D.H. et al. Co-transplantation of bone marrow-derived mesenchymal stem cells and nanospheres containing FGF-2 improve cell survival and neurological function in the injured rat spinal cord. Acta Neurochir 156, 297–303 (2014). https://doi.org/10.1007/s00701-013-1963-y