Human umbilical cord blood mononuclear cells and chorionic plate-derived mesenchymal stem cells promote axon survival
in a rat model of optic nerve crush injury

Chung,Sokjoong; Rho,Seungsoo; Kim,Gijin; Kim,So-Ra; Baek,Kwang-Hyun; Kang,Myungseo; Lew,Helen

doi:10.3892/ijmm.2016.2532

Human umbilical cord blood mononuclear cells and chorionic plate-derived mesenchymal stem cells promote axon survival in a rat model of optic nerve crush injury

Authors:
- Sokjoong Chung
- Seungsoo Rho
- Gijin Kim
- So-Ra Kim
- Kwang-Hyun Baek
- Myungseo Kang
- Helen Lew
View Affiliations

Affiliations: Department of Ophthalmology, CHA Bundang Medical Center, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea, Department of Biomedical Science, CHA Bundang Medical Center, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea, Department of Laboratory Medicine, CHA Bundang Medical Center, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea
Published online on: March 17, 2016 https://doi.org/10.3892/ijmm.2016.2532
Pages: 1170-1180
Copyright: © Chung et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The use of mesenchymal stem cells (MSCs) in cell therapy in regenerative medicine has great potential, particularly in the treatment of nerve injury. Umbilical cord blood (UCB) reportedly contains stem cells, which have been widely used as a hematopoietic source and may have therapeutic potential for neurological impairment. Although ongoing research is dedicated to the management of traumatic optic nerve injury using various measures, novel therapeutic strategies based on the complex underlying mechanisms responsible for optic nerve injury, such as inflammation and/or ischemia, are required. In the present study, a rat model of optic nerve crush (ONC) injury was established in order to examine the effects of transplanting human chorionic plate-derived MSCs (CP‑MSCs) isolated from the placenta, as well as human UCB mononuclear cells (CB-MNCs) on compressed rat optic nerves. Expression markers for inflammation, apoptosis, and optic nerve regeneration were analyzed, as well as the axon survival rate by direct counting. Increased axon survival rates were observed following the injection of CB‑MNCs at at 1 week post-transplantation compared with the controls. The levels of growth-associated protein-43 (GAP‑43) were increased after the injection of CB‑MNCs or CP‑MSCs compared with the controls, and the expression levels of hypoxia-inducible factor-1α (HIF-1α) were also significantly increased following the injection of CB-MNCs or CP-MSCs. ERM-like protein (ERMN) and SLIT-ROBO Rho GTPase activating protein 2 (SRGAP2) were found to be expressed in the optic nerves of the CP‑MSC-injected rats with ONC injury. The findings of our study suggest that the administration of CB‑MNCs or CP‑MSCs may promote axon survival through systemic concomitant mechanisms involving GAP‑43 and HIF‑1α. Taken together, these findings provide further understanding of the mechanisms repsonsible for optic nerve injury and may aid in the development of novel cell-based therapeutic strategies with future applications in regenerative medicine, particularly in the management of optic nerve disorders.

View Figures

View References

1	Zhao T, Li Y, Tang L, Li Y, Fan F and Jiang B: Protective effects of human umbilical cord blood stem cell intravitreal transplantation against optic nerve injury in rats. Graefes Arch Clin Exp Ophthalmol. 249:1021–1028. 2011. View Article : Google Scholar : PubMed/NCBI
2	Junyi L, Na L and Yan J: Mesenchymal stem cells secrete brain-derived neurotrophic factor and promote retinal ganglion cell survival after traumatic optic neuropathy. J Craniofac Surg. 26:548–552. 2015. View Article : Google Scholar : PubMed/NCBI
3	Bull ND, Irvine KA, Franklin RJ and Martin KR: Transplanted oligodendrocyte precursor cells reduce neurodegeneration in a model of glaucoma. Invest Ophthalmol Vis Sci. 50:4244–4253. 2009. View Article : Google Scholar : PubMed/NCBI
4	Aoki H, Hara A, Niwa M, Motohashi T, Suzuki T and Kunisada T: Transplantation of cells from eye-like structures differentiated from embryonic stem cells in vitro and in vivo regeneration of retinal ganglion-like cells. Graefes Arch Clin Exp Ophthalmol. 246:255–265. 2008. View Article : Google Scholar
5	Bull ND, Limb GA and Martin KR: Human Müller stem cell (MIO-M1) transplantation in a rat model of glaucoma: survival, differentiation, and integration. Invest Ophthalmol Vis Sci. 49:3449–3456. 2008. View Article : Google Scholar : PubMed/NCBI
6	Levkovitch-Verbin H, Sadan O, Vander S, Rosner M, Barhum Y, Melamed E, Offen D and Melamed S: Intravitreal injections of neurotrophic factors secreting mesenchymal stem cells are neuroprotective in rat eyes following optic nerve transection. Invest Ophthalmol Vis Sci. 51:6394–6400. 2010. View Article : Google Scholar : PubMed/NCBI
7	Charalambous P, Hurst LA and Thanos S: Engrafted chicken neural tube-derived stem cells support the innate propensity for axonal regeneration within the rat optic nerve. Invest Ophthalmol Vis Sci. 49:3513–3524. 2008. View Article : Google Scholar : PubMed/NCBI
8	Canque B, Camus S, Dalloul A, Kahn E, Yagello M, Dezutter-Dambuyant C, Schmitt D, Schmitt C and Gluckman JC: Characterization of dendritic cell differentiation pathways from cord blood CD34(+)CD7(+)CD45RA(+) hematopoietic progenitor cells. Blood. 96:3748–3756. 2000.PubMed/NCBI
9	Kao CH, Chen SH, Chio CC and Lin MT: Human umbilical cord blood-derived CD34⁺ cells may attenuate spinal cord injury by stimulating vascular endothelial and neurotrophic factors. Shock. 29:49–55. 2008.
10	Lee MW, Jang IK, Yoo KH, Sung KW and Koo HH: Stem and progenitor cells in human umbilical cord blood. Int J Hematol. 92:45–51. 2010. View Article : Google Scholar : PubMed/NCBI
11	Min K, Song J, Kang JY, Ko J, Ryu JS, Kang MS, Jang SJ, Kim SH, Oh D, Kim MK, et al: Umbilical cord blood therapy potentiated with erythropoietin for children with cerebral palsy: a double-blind, randomized, placebo-controlled trial. Stem Cells. 31:581–591. 2013. View Article : Google Scholar : PubMed/NCBI
12	Newcomb JD, Sanberg PR, Klasko SK and Willing AE: Umbilical cord blood research: current and future perspectives. Cell Transplant. 16:151–158. 2007.PubMed/NCBI
13	Lu D, Sanberg PR, Mahmood A, Li Y, Wang L, Sanchez-Ramos J and Chopp M: Intravenous administration of human umbilical cord blood reduces neurological deficit in the rat after traumatic brain injury. Cell Transplant. 11:275–281. 2002.PubMed/NCBI
14	Meier C, Middelanis J, Wasielewski B, Neuhoff S, Roth-Haerer A, Gantert M, Dinse HR, Dermietzel R and Jensen A: Spastic paresis after perinatal brain damage in rats is reduced by human cord blood mononuclear cells. Pediatr Res. 59:244–249. 2006. View Article : Google Scholar : PubMed/NCBI
15	Nan Z, Grande A, Sanberg CD, Sanberg PR and Low WC: Infusion of human umbilical cord blood ameliorates neurologic deficits in rats with hemorrhagic brain injury. Ann N Y Acad Sci. 1049:84–96. 2005. View Article : Google Scholar : PubMed/NCBI
16	Nikolic WV, Hou H, Town T, Zhu Y, Giunta B, Sanberg CD, Zeng J, Luo D, Ehrhart J, Mori T, et al: Peripherally administered human umbilical cord blood cells reduce parenchymal and vascular beta-amyloid deposits in Alzheimer mice. Stem Cells Dev. 17:423–439. 2008. View Article : Google Scholar : PubMed/NCBI
17	Papadopoulos KI, Low SS, Aw TC and Chantarojanasiri T: Safety and feasibility of autologous umbilical cord blood transfusion in 2 toddlers with cerebral palsy and the role of low dose granulocyte-colony stimulating factor injections. Restor Neurol Neurosci. 29:17–22. 2011.PubMed/NCBI
18	Sun J, Allison J, McLaughlin C, Sledge L, Waters-Pick B, Wease S and Kurtzberg J: Differences in quality between privately and publicly banked umbilical cord blood units: a pilot study of autologous cord blood infusion in children with acquired neurologic disorders. Transfusion. 50:1980–1987. 2010. View Article : Google Scholar : PubMed/NCBI
19	Vendrame M, Cassady J, Newcomb J, Butler T, Pennypacker KR, Zigova T, Sanberg CD, Sanberg PR and Willing AE: Infusion of human umbilical cord blood cells in a rat model of stroke dose-dependently rescues behavioral deficits and reduces infarct volume. Stroke. 35:2390–2395. 2004. View Article : Google Scholar : PubMed/NCBI
20	Kim MJ, Shin KS, Jeon JH, Lee DR, Shim SH, Kim JK, Cha DH, Yoon TK and Kim GJ: Human chorionic-plate-derived mesenchymal stem cells and Wharton's jelly-derived mesenchymal stem cells: a comparative analysis of their potential as placenta-derived stem cells. Cell Tissue Res. 346:53–64. 2011. View Article : Google Scholar : PubMed/NCBI
21	Lee JM, Jung J, Lee HJ, Jeong SJ, Cho KJ, Hwang SG and Kim GJ: Comparison of immunomodulatory effects of placenta mesenchymal stem cells with bone marrow and adipose mesenchymal stem cells. Int Immunopharmacol. 13:219–224. 2012. View Article : Google Scholar : PubMed/NCBI
22	Parolini O, Alviano F, Bagnara GP, Bilic G, Bühring HJ, Evangelista M, Hennerbichler S, Liu B, Magatti M, Mao N, et al: Concise review: isolation and characterization of cells from human term placenta: outcome of the first international Workshop on Placenta Derived Stem Cells. Stem Cells. 26:300–311. 2008. View Article : Google Scholar
23	Jung J, Choi JH, Lee Y, Park JW, Oh IH, Hwang SG, Kim KS and Kim GJ: Human placenta-derived mesenchymal stem cells promote hepatic regeneration in CCl₄-injured rat liver model via increased autophagic mechanism. Stem Cells. 31:1584–1596. 2013. View Article : Google Scholar : PubMed/NCBI
24	Lee MJ, Jung J, Na KH, Moon JS, Lee HJ, Kim JH, Kim GI, Kwon SW, Hwang SG and Kim GJ: Anti-fibrotic effect of chorionic plate-derived mesenchymal stem cells isolated from human placenta in a rat model of CCl₄-injured liver: potential application to the treatment of hepatic diseases. J Cell Biochem. 111:1453–1463. 2010. View Article : Google Scholar : PubMed/NCBI
25	Koriyama Y, Homma K, Sugitani K, Higuchi Y, Matsukawa T, Murayama D and Kato S: Upregulation of IGF-I in the goldfish retinal ganglion cells during the early stage of optic nerve regeneration. Neurochem Int. 50:749–756. 2007. View Article : Google Scholar : PubMed/NCBI
26	Benowitz LI and Yin Y: Optic nerve regeneration. Arch Ophthalmol. 128:1059–1064. 2010. View Article : Google Scholar : PubMed/NCBI
27	Tajima T, Goda N, Fujiki N, Hishiki T, Nishiyama Y, Senoo-Matsuda N, Shimazu M, Soga T, Yoshimura Y, Johnson RS and Suematsu M: HIF-1alpha is necessary to support gluconeogenesis during liver regeneration. Biochem Biophys Res Commun. 387:789–794. 2009. View Article : Google Scholar : PubMed/NCBI
28	Booij JC, ten Brink JB, Swagemakers SM, Verkerk AJ, Essing AH, van der Spek PJ and Bergen AA: A new strategy to identify and annotate human RPE-specific gene expression. PLoS One. 5:e93412010. View Article : Google Scholar : PubMed/NCBI
29	Guerrier S, Coutinho-Budd J, Sassa T, Gresset A, Jordan NV, Chen K, Jin WL, Frost A and Polleux F: The F-BAR domain of srGAP2 induces membrane protrusions required for neuronal migration and morphogenesis. Cell. 138:990–1004. 2009. View Article : Google Scholar : PubMed/NCBI
30	Dennis MY, Nuttle X, Sudmant PH, Antonacci F, Graves TA, Nefedov M, Rosenfeld JA, Sajjadian S, Malig M, Kotkiewicz H, et al: Evolution of human-specific neural SRGAP2 genes by incomplete segmental duplication. Cell. 149:912–922. 2012. View Article : Google Scholar : PubMed/NCBI
31	Kato S, Devadas M, Okada K, Shimada Y, Ohkawa M, Muramoto K, Takizawa N and Matsukawa T: Fast and slow recovery phases of goldfish behavior after transection of the optic nerve revealed by a computer image processing system. Neuroscience. 93:907–914. 1999. View Article : Google Scholar : PubMed/NCBI
32	Johnson TV, Bull ND, Hunt DP, Marina N, Tomarev SI and Martin KR: Neuroprotective effects of intravitreal mesenchymal stem cell transplantation in experimental glaucoma. Invest Ophthalmol Vis Sci. 51:2051–2059. 2010. View Article : Google Scholar :
33	Ebneter A, Casson RJ, Wood JP and Chidlow G: Estimation of axon counts in a rat model of glaucoma: comparison of fixed-pattern sampling with targeted sampling. Clin Experiment Ophthalmol. 40:626–633. 2012. View Article : Google Scholar
34	Kim CY, Rho S, Lee NE, Lee CK and Sung YJ: Semi-automated counting method of axons in transmission electron microscopic images. Vet Ophthalmol. 19:29–37. 2016. View Article : Google Scholar
35	Rho S, Park I, Seong GJ, Lee N, Lee CK, Hong S and Kim CY: Chronic ocular hypertensive rat model using microbead injection: comparison of polyurethane, polymethylmethacrylate, silica and polystyene microbeads. Curr Eye Res. 39:917–927. 2014. View Article : Google Scholar : PubMed/NCBI
36	Kaneda M, Nagashima M, Mawatari K, Nunome T, Muramoto K, Sugitani K and Kato S: Growth-associated protein43 (GAP43) is a biochemical marker for the whole period of fish optic nerve regeneration. Adv Exp Med Biol. 664:97–104. 2010. View Article : Google Scholar : PubMed/NCBI
37	Vollmer S, Kappler V, Kaczor J, Flügel D, Rolvering C, Kato N, Kietzmann T, Behrmann I and Haan C: Hypoxia-inducible factor 1alpha is up-regulated by oncostatin M and participates in oncostatin M signaling. Hepatology. 50:253–260. 2009. View Article : Google Scholar : PubMed/NCBI
38	Hellwig-Bürgel T, Stiehl DP, Wagner AE, Metzen E and Jelkmann W: Review: hypoxia-inducible factor-1 (HIF-1): a novel transcription factor in immune reactions. J Interferon Cytokine Res. 25:297–310. 2005. View Article : Google Scholar : PubMed/NCBI
39	Kinnaird T, Stabile E, Burnett MS, Shou M, Lee CW, Barr S, Fuchs S and Epstein SE: Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation. 109:1543–1549. 2004. View Article : Google Scholar : PubMed/NCBI
40	Gnecchi M, He H, Liang OD, Melo LG, Morello F, Mu H, Noiseux N, Zhang L, Pratt RE, Ingwall JS and Dzau VJ: Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med. 11:367–368. 2005. View Article : Google Scholar : PubMed/NCBI
41	Kinnaird T, Stabile E, Burnett MS, Lee CW, Barr S, Fuchs S and Epstein SE: Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ Res. 94:678–685. 2004. View Article : Google Scholar : PubMed/NCBI
42	O'Neill TJ IV, Wamhoff BR, Owens GK and Skalak TC: Mobilization of bone marrow-derived cells enhances the angiogenic response to hypoxia without transdifferentiation into endothelial cells. Circ Res. 97:1027–1035. 2005. View Article : Google Scholar : PubMed/NCBI
43	Terada N, Hamazaki T, Oka M, Hoki M, Mastalerz DM, Nakano Y, Meyer EM, Morel L, Petersen BE and Scott EW: Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature. 416:542–545. 2002. View Article : Google Scholar : PubMed/NCBI
44	Uemura R, Xu M, Ahmad N and Ashraf M: Bone marrow stem cells prevent left ventricular remodeling of ischemic heart through paracrine signaling. Circ Res. 98:1414–1421. 2006. View Article : Google Scholar : PubMed/NCBI
45	Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, Fike JR, Lee HO, Pfeffer K, Lois C, Morrison SJ and Alvarez-Buylla A: Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature. 425:968–973. 2003. View Article : Google Scholar : PubMed/NCBI
46	Nygren JM, Jovinge S, Breitbach M, Säwén P, Röll W, Hescheler J, Taneera J, Fleischmann BK and Jacobsen SE: Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nat Med. 10:494–501. 2004. View Article : Google Scholar : PubMed/NCBI
47	Li C, Zhang W, Jiang X and Mao N: Human-placenta-derived mesenchymal stem cells inhibit proliferation and function of allogeneic immune cells. Cell Tissue Res. 330:437–446. 2007. View Article : Google Scholar : PubMed/NCBI
48	Sanchez CG, Penfornis P, Oskowitz AZ, Boonjindasup AG, Cai DZ, Dhule SS, Rowan BG, Kelekar A, Krause DS and Pochampally RR: Activation of autophagy in mesenchymal stem cells provides tumor stromal support. Carcinogenesis. 32:964–972. 2011. View Article : Google Scholar : PubMed/NCBI
49	Lee Y, Jung J, Cho KJ, Lee SK, Park JW, Oh IH and Kim GJ: Increased SCF/c-kit by hypoxia promotes autophagy of human placental chorionic plate-derived mesenchymal stem cells via regulating the phosphorylation of mTOR. J Cell Biochem. 114:79–88. 2013. View Article : Google Scholar
50	Gornicka-Pawlak el B, Janowski M, Habich A, Jablonska A, Drela K, Kozlowska H, Lukomska B, Sypecka J and Domanska-Janik K: Systemic treatment of focal brain injury in the rat by human umbilical cord blood cells being at different level of neural commitment. Acta Neurobiol Exp (Wars). 71:46–64. 2011.
51	Gijtenbeek JM, van den Bent MJ and Vecht CJ: Cyclosporine neurotoxicity: A review. J Neurol. 246:339–346. 1999. View Article : Google Scholar : PubMed/NCBI