Open Access

Therapeutic effect of transplantation of human bone marrow‑derived mesenchymal stem cells on neuron regeneration in a rat model of middle cerebral artery occlusion

  • Authors:
    • Ping Xie
    • Ming Deng
    • Qin‑Guo Sun
    • Yong‑Gang Ma
    • Yan Zhou
    • Jiang‑Hua Ming
    • Qing Chen
    • Shi‑Qing Liu
    • Jun‑Qi Liu
    • Jun Cai
    • Fei Wu
  • View Affiliations

  • Published online on: July 30, 2019     https://doi.org/10.3892/mmr.2019.10536
  • Pages: 3065-3074
  • Copyright: © Xie 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: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Human bone marrow‑derived mesenchymal stromal cells (hBMSCs) have been revealed to be beneficial for the regeneration of tissues and cells in several diseases. The present study aimed to elucidate the mechanisms underlying the effect of hBMSC transplantation on neuron regeneration in a rat model of middle cerebral artery occlusion (MCAO). The hBMSCs were isolated, cultured and identified. A rat model of MCAO was induced via the modified Longa method. Neurological severity scores (NSS) were adopted for the evaluation of neuronal function in the model rats after cell transplantation. Next, the expression levels of nestin, β‑III‑tubulin (β‑III‑Tub), glial fibrillary acidic protein (GFAP), HNA and neuronal nuclear antigen (NeuN) were examined, as well as the positive expression rates of human neutrophil alloantigen (HNA), nestin, NeuN, β‑III‑Tub and GFAP. The NSS, as well as the mRNA and protein expression of nestin, decreased at the 1st, 2nd, 4 and 8th weeks, while the mRNA and protein expression of NeuN, β‑III‑Tub and GFAP increased with time. In addition, after treatment, the MCAO rats showed decreased NSS and mRNA and protein expression of nestin, but elevated mRNA and protein expression of NeuN, β‑III‑Tub and GFAP at the 2nd, 4 and 8th weeks, and decreased positive expression of HNA and nestin with enhanced expression of NeuN, β‑III‑Tub and GFAP. Therefore, the present findings demonstrated that hBMSC transplantation triggered the formation of nerve cells and enhanced neuronal function in a rat model of MCAO.

References

1 

Gibson CL: Cerebral ischemic stroke: Is gender important? J Cereb Blood Flow Metab. 33:1355–1361. 2013. View Article : Google Scholar : PubMed/NCBI

2 

Fann DY, Lee SY, Manzanero S, Tang SC, Gelderblom M, Chunduri P, Bernreuther C, Glatzel M, Cheng YL, Thundyil J, et al: Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke. Cell Death Dis. 4:e7902013. View Article : Google Scholar : PubMed/NCBI

3 

Cho HY, Kim JS and Lee GC: Effects of motor imagery training on balance and gait abilities in post-stroke patients: A randomized controlled trial. Clin Rehabil. 27:675–680. 2013. View Article : Google Scholar : PubMed/NCBI

4 

Metrot J, Mottet D, Hauret I, van Dokkum L, Bonnin-Koang HY, Torre K and Laffont I: Changes in bimanual coordination during the first 6 weeks after moderate hemiparetic stroke. Neurorehabil Neural Repair. 27:251–259. 2013. View Article : Google Scholar : PubMed/NCBI

5 

Becker L and Mashimo H: Further promise of stem cells therapies in the enteric nervous system. Gastroenterology. 136:2055–2058. 2009. View Article : Google Scholar : PubMed/NCBI

6 

Kulkarni S, Becker L and Pasricha PJ: Stem cell transplantation in neurodegenerative disorders of the gastrointestinal tract: Future or fiction? Gut. 61:613–621. 2012. View Article : Google Scholar : PubMed/NCBI

7 

Garbossa D, Boido M, Fontanella M, Fronda C, Ducati A and Vercelli A: Recent therapeutic strategies for spinal cord injury treatment: Possible role of stem cells. Neurosurg Rev. 35:D293–D311. 2012. View Article : Google Scholar

8 

Maitland GD: The slump test: Examination and treatment. Aust J Physiother. 31:215–219. 1985. View Article : Google Scholar : PubMed/NCBI

9 

Lin R, Ding Z, Ma H, Shi H, Gao Y, Qian W, Shi W, Sun Z, Hou X and Li X: In vitro conditioned bone marrow-derived mesenchymal stem cells promote de novo functional enteric nerve regeneration, but not through direct-transdifferentiation. Stem Cells. 33:3545–3557. 2015. View Article : Google Scholar : PubMed/NCBI

10 

Yamasaki S, Mera H, Itokazu M, Hashimoto Y and Wakitani S: Cartilage repair with autologous bone marrow mesenchymal stem cell transplantation: Review of preclinical and clinical studies. Cartilage. 5:196–200. 2014. View Article : Google Scholar : PubMed/NCBI

11 

Chen L, Qu J and Xiang C: The multi-functional roles of menstrual blood-derived stem cells in regenerative medicine. Stem Cell Res Ther. 10:12019. View Article : Google Scholar : PubMed/NCBI

12 

Maxson S, Lopez EA, Yoo D, Danilkovitch-Miagkova A and Leroux MA: Concise review: Role of mesenchymal stem cells in wound repair. Stem Cells Transl Med. 1:142–149. 2012. View Article : Google Scholar : PubMed/NCBI

13 

Tuan RS, Boland G and Tuli R: Adult mesenchymal stem cells and cell-based tissue engineering. Arthritis Res Ther. 5:32–45. 2003. View Article : Google Scholar : PubMed/NCBI

14 

Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S and Marshak DR: Multilineage potential of adult human mesenchymal stem cells. Science. 284:143–147. 1999. View Article : Google Scholar : PubMed/NCBI

15 

Vanden Berg-Foels WS: In situ tissue regeneration: Chemoattractants for endogenous stem cell recruitment. Tissue Eng Part B Rev. 20:28–39. 2014. View Article : Google Scholar : PubMed/NCBI

16 

Xu M, Stattin EL, Shaw G, Heinegard D, Sullivan G, Wilmut I, Colman A, Önnerfjord P, Khabut A, Aspberg A, et al: Chondrocytes derived from mesenchymal stromal cells and induced pluripotent cells of patients with familial osteochondritis dissecans exhibit an endoplasmic reticulum stress response and defective matrix assembly. Stem Cells Transl Med. 5:1171–1181. 2016. View Article : Google Scholar : PubMed/NCBI

17 

Lindvall O and Kokaia Z: Stem cells in human neurodegenerative disorders--time for clinical translation? J Clin Invest. 120:29–40. 2010. View Article : Google Scholar : PubMed/NCBI

18 

Scuteri A, Miloso M, Foudah D, Orciani M, Cavaletti G and Tredici G: Mesenchymal stem cells neuronal differentiation ability: A real perspective for nervous system repair? Curr Stem Cell Res Ther. 6:82–92. 2011. View Article : Google Scholar : PubMed/NCBI

19 

Trzaska KA, King CC, Li KY, Kuzhikandathil EV, Nowycky MC, Ye JH and Rameshwar P: Brain-derived neurotrophic factor facilitates maturation of mesenchymal stem cell-derived dopamine progenitors to functional neurons. J Neurochem. 110:1058–1069. 2009. View Article : Google Scholar : PubMed/NCBI

20 

Greco SJ, Zhou C, Ye JH and Rameshwar P: An interdisciplinary approach and characterization of neuronal cells transdifferentiated from human mesenchymal stem cells. Stem Cells Dev. 16:811–826. 2007. View Article : Google Scholar : PubMed/NCBI

21 

Singer NG and Caplan AI: Mesenchymal stem cells: Mechanisms of inflammation. Annu Rev Pathol. 6:457–478. 2011. View Article : Google Scholar : PubMed/NCBI

22 

Uccelli A, Moretta L and Pistoia V: Mesenchymal stem cells in health and disease. Nat Rev Immunol. 8:726–736. 2008. View Article : Google Scholar : PubMed/NCBI

23 

Tohill M, Mantovani C, Wiberg M and Terenghi G: Rat bone marrow mesenchymal stem cells express glial markers and stimulate nerve regeneration. Neurosci Lett. 362:200–203. 2004. View Article : Google Scholar : PubMed/NCBI

24 

Liu F and McCullough LD: Middle cerebral artery occlusion model in rodents: Methods and potential pitfalls. J Biomed Biotechnol. 2011:4647012011. View Article : Google Scholar : PubMed/NCBI

25 

Zhang QW, Deng XX, Sun X, Xu JX and Sun FY: Exercise promotes axon regeneration of newborn striatonigral and corticonigral projection neurons in rats after ischemic stroke. PLoS One. 8:e801392013. View Article : Google Scholar : PubMed/NCBI

26 

Bao X, Wei J, Feng M, Lu S, Li G, Dou W, Ma W, Ma S, An Y, Qin C, et al: Transplantation of human bone marrow-derived mesenchymal stem cells promotes behavioral recovery and endogenous neurogenesis after cerebral ischemia in rats. Brain Res. 1367:103–113. 2011. View Article : Google Scholar : PubMed/NCBI

27 

He XY, Chen ZZ, Cai YQ, Xu G, Shang JH, Kou SB, Li M, Zhang HT, Duan CZ, Zhang SZ, et al: Expression of cytokines in rat brain with focal cerebral ischemia after grafting with bone marrow stromal cells and endothelial progenitor cells. Cytotherapy. 13:46–53. 2011. View Article : Google Scholar : PubMed/NCBI

28 

Mathivanan I, Trepp C, Brunold C, Baerlocher G and Enzmann V: Retinal differentiation of human bone marrow-derived stem cells by co-culture with retinal pigment epithelium in vitro. Exp Cell Res. 333:11–20. 2015. View Article : Google Scholar : PubMed/NCBI

29 

Longa EZ, Weinstein PR, Carlson S and Cummins R: Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke. 20:84–91. 1989. View Article : Google Scholar : PubMed/NCBI

30 

McSweeney C and Mao Y: Applying stereotactic injection technique to study genetic effects on animal behaviors. J Vis Exp. e526532015.PubMed/NCBI

31 

Chen J, Sanberg PR, Li Y, Wang L, Lu M, Willing AE, Sanchez-Ramos J and Chopp M: Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats. Stroke. 32:2682–2688. 2001. View Article : Google Scholar : PubMed/NCBI

32 

Honma T, Honmou O, Iihoshi S, Harada K, Houkin K, Hamada H and Kocsis JD: Intravenous infusion of immortalized human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat. Exp Neurol. 199:56–66. 2006. View Article : Google Scholar : PubMed/NCBI

33 

Hou M, Yang KM, Zhang H, Zhu WQ, Duan FJ, Wang H, Song YH, Wei YJ and Hu SS: Transplantation of mesenchymal stem cells from human bone marrow improves damaged heart function in rats. Int J Cardiol. 115:220–228. 2007. View Article : Google Scholar : PubMed/NCBI

34 

Vital SA and Gavins FN: Surgical Approach for middle cerebral artery occlusion and reperfusion induced stroke in mice. J Vis Exp. 2016. View Article : Google Scholar : PubMed/NCBI

35 

Wakabayashi K, Nagai A, Sheikh AM, Shiota Y, Narantuya D, Watanabe T, Masuda J, Kobayashi S, Kim SU and Yamaguchi S: Transplantation of human mesenchymal stem cells promotes functional improvement and increased expression of neurotrophic factors in a rat focal cerebral ischemia model. J Neurosci Res. 88:1017–1025. 2010.PubMed/NCBI

36 

Wei L, Fraser JL, Lu ZY, Hu X and Yu SP: Transplantation of hypoxia preconditioned bone marrow mesenchymal stem cells enhances angiogenesis and neurogenesis after cerebral ischemia in rats. Neurobiol Dis. 46:635–645. 2012. View Article : Google Scholar : PubMed/NCBI

37 

Ma M, Ma Y, Yi X, Guo R, Zhu W, Fan X, Xu G, Frey WH 2nd and Liu X: Intranasal delivery of transforming growth factor-beta1 in mice after stroke reduces infarct volume and increases neurogenesis in the subventricular zone. BMC Neurosci. 9:1172008. View Article : Google Scholar : PubMed/NCBI

38 

Chen J, Li Y, Wang L, Lu M, Zhang X and Chopp M: Therapeutic benefit of intracerebral transplantation of bone marrow stromal cells after cerebral ischemia in rats. J Neurol Sci. 189:49–57. 2001. View Article : Google Scholar : PubMed/NCBI

39 

Cha HK, Cho HS and Choi JD: Effects of the nerve mobilization technique on lower limb function in patients with poststroke hemiparesis. J Phys Ther Sci. 26:981–983. 2014. View Article : Google Scholar : PubMed/NCBI

40 

Rola R, Mizumatsu S, Otsuka S, Morhardt DR, Noble-Haeusslein LJ, Fishman K, Potts MB and Fike JR: Alterations in hippocampal neurogenesis following traumatic brain injury in mice. Exp Neurol. 202:189–199. 2006. View Article : Google Scholar : PubMed/NCBI

41 

Ohnuma S and Harris WA: Neurogenesis and the cell cycle. Neuron. 40:199–208. 2003. View Article : Google Scholar : PubMed/NCBI

42 

Alvarez-Buylla A and Lim DA: For the long run: Maintaining germinal niches in the adult brain. Neuron. 41:683–686. 2004. View Article : Google Scholar : PubMed/NCBI

43 

Lindvall O and Kokaia Z: Stem cells for the treatment of neurological disorders. Nature. 441:1094–1096. 2006. View Article : Google Scholar : PubMed/NCBI

44 

Segal-Gavish H, Karvat G, Barak N, Barzilay R, Ganz J, Edry L, Aharony I, Offen D and Kimchi T: Mesenchymal stem cell transplantation promotes neurogenesis and ameliorates autism related behaviors in BTBR mice. Autism Res. 9:17–32. 2016. View Article : Google Scholar : PubMed/NCBI

45 

Ishiwata T, Matsuda Y and Naito Z: Nestin in gastrointestinal and other cancers: Effects on cells and tumor angiogenesis. World J Gastroenterol. 17:409–418. 2011. View Article : Google Scholar : PubMed/NCBI

46 

Krylyshkina O, Chen J, Mebis L, Denef C and Vankelecom H: Nestin-immunoreactive cells in rat pituitary are neither hormonal nor typical folliculo-stellate cells. Endocrinology. 146:2376–2387. 2005. View Article : Google Scholar : PubMed/NCBI

47 

Honda M, Tsuruta R, Kaneko T, Kasaoka S, Yagi T, Todani M, Fujita M, Izumi T and Maekawa T: Serum glial fibrillary acidic protein is a highly specific biomarker for traumatic brain injury in humans compared with S-100B and neuron-specific enolase. J Trauma. 69:104–109. 2010. View Article : Google Scholar : PubMed/NCBI

48 

Lavezzi AM, Corna MF and Matturri L: Neuronal nuclear antigen (NeuN): A useful marker of neuronal immaturity in sudden unexplained perinatal death. J Neurol Sci. 329:45–50. 2013. View Article : Google Scholar : PubMed/NCBI

49 

Gusel'nikova VV and Korzhevskiy DE: NeuN as a neuronal nuclear antigen and neuron differentiation marker. Acta Naturae. 7:42–47. 2015. View Article : Google Scholar : PubMed/NCBI

50 

Kucia M, Zhang YP, Reca R, Wysoczynski M, Machalinski B, Majka M, Ildstad ST, Ratajczak J, Shields CB and Ratajczak MZ: Cells enriched in markers of neural tissue-committed stem cells reside in the bone marrow and are mobilized into the peripheral blood following stroke. Leukemia. 20:18–28. 2006. View Article : Google Scholar : PubMed/NCBI

51 

Oh SH, Kim HN, Park HJ, Shin JY and Lee PH: Mesenchymal stem cells increase hippocampal neurogenesis and neuronal differentiation by enhancing the wnt signaling pathway in an Alzheimer's disease model. Cell Transplant. 24:1097–1109. 2015. View Article : Google Scholar : PubMed/NCBI

52 

Shafei AE, Ali MA, Ghanem HG, Shehata AI, Abdelgawad AA, Handal HR, Talaat KA, Ashaal AE and El-Shal AS: Mesenchymal stem cell therapy: A promising cell-based therapy for treatment of myocardial infarction. J Gene Med. 19:2017. View Article : Google Scholar : PubMed/NCBI

53 

Fiore EJ, Domínguez LM, Bayo J, García MG and Mazzolini GD: Taking advantage of the potential of mesenchymal stromal cells in liver regeneration: Cells and extracellular vesicles as therapeutic strategies. World J Gastroenterol. 24:2427–2440. 2018. View Article : Google Scholar : PubMed/NCBI

54 

Meirelles Lda S, Fontes AM, Covas DT and Caplan AI: Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev. 20:419–427. 2009. View Article : Google Scholar : PubMed/NCBI

55 

Karow M, Sánchez R, Schichor C, Masserdotti G, Ortega F, Heinrich C, Gascón S, Khan MA, Lie DC, Dellavalle A, et al: Reprogramming of pericyte-derived cells of the adult human brain into induced neuronal cells. Cell Stem Cell. 11:471–476. 2012. View Article : Google Scholar : PubMed/NCBI

56 

Crisan M, Yap S, Casteilla L, Chen CW, Corselli M, Park TS, Andriolo G, Sun B, Zheng B, Zhang L, et al: A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell. 3:301–313. 2008. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

October 2019
Volume 20 Issue 4

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Xie, P., Deng, M., Sun, Q., Ma, Y., Zhou, Y., Ming, J. ... Wu, F. (2019). Therapeutic effect of transplantation of human bone marrow‑derived mesenchymal stem cells on neuron regeneration in a rat model of middle cerebral artery occlusion. Molecular Medicine Reports, 20, 3065-3074. https://doi.org/10.3892/mmr.2019.10536
MLA
Xie, P., Deng, M., Sun, Q., Ma, Y., Zhou, Y., Ming, J., Chen, Q., Liu, S., Liu, J., Cai, J., Wu, F."Therapeutic effect of transplantation of human bone marrow‑derived mesenchymal stem cells on neuron regeneration in a rat model of middle cerebral artery occlusion". Molecular Medicine Reports 20.4 (2019): 3065-3074.
Chicago
Xie, P., Deng, M., Sun, Q., Ma, Y., Zhou, Y., Ming, J., Chen, Q., Liu, S., Liu, J., Cai, J., Wu, F."Therapeutic effect of transplantation of human bone marrow‑derived mesenchymal stem cells on neuron regeneration in a rat model of middle cerebral artery occlusion". Molecular Medicine Reports 20, no. 4 (2019): 3065-3074. https://doi.org/10.3892/mmr.2019.10536