Abstract
The ability of mesenchymal stem cells (MSCs) to differentiate into neuronal lineage determines the potential of these cells as a substrate for a cell replacement therapy. In this paper we compare the neurogenic potential of the MSCs from different donors, isolated from the bone marrow (BMSC), subcutaneous adipose tissue (AD MSC) and menstrual blood (eMSC). It was established that the native eMCSs, BMSCs and AD MSCs express neuronal marker β-III-tubulin with a frequency of 90, 50 and 14%, respectively. Also we showed that the eMSCs have a high endogenous level of brain-derived neurotrophic factor (BDNF), whereas the BMSCs and the AD MSCs are characterized by low basal BDNF levels. An induction of neuronal differentiation in the studied MSCs using differentiation medium containing B27 and N2 supplements, 5-azacytidine, retinoic acid, IBMX and dbcAMP induced changes in the cells morphology, the increase of β-III-tubulin expression, and the appearance of neuronal markers GFAP, NF-H, NeuN and MAP2. During the differentiation the BDNF secretion was significantly enhanced in the BMSCs and decreased in the eMSCs cultures. However, no correlation between the basal and induced levels of the neuronal markers expression in the studied MSCs has been established.
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Abbreviations
- BM:
-
bone marrow
- AD:
-
adipose tissue
- MSCs:
-
mesenchymal stem cells
- eMSC:
-
endometrial MSCs
- BMSCs:
-
bone marrow MSCs
- AD MSCs:
-
MSCs from adipose tissue
- GFAP:
-
glial fibrillary acidic protein
- NF-H:
-
neuronal filaments
- NeuN:
-
neuronal nuclei
- MAP2:
-
protein associated with microtubules
- IBMX:
-
isobutylmethylxanthine
- dbcAMP:
-
dibutyryl-cyclic AMP
References
Acheson, A., Conover, J.C., Fandl, J.P., DeChiara, T.M., Russell, M., Thadani, A., Squinto, S.P., Yancopoulos, G.D., and Lindsay, R.M., A BDNF autocrine loop in adult sensory neurons prevents cell death, Nature, 1995, vol. 374, pp. 450–453.
Anghileri, E., Marconi, S., Pignatelli, A., Cifelli, P., Galie, M., and Sbarbati, A., Neuronal differentiation potential of human adiposederived mesenchymal stem cells, Stem Cells Dev., 2008, vol. 17, no. 5, pp. 909–916.
Blandini, F., Cova, L., Armentero, M.T., Zennaro, E., Levandis, G., Bossolasco, P., Calzarossa, C., Mellone, M., Giuseppe, B., Deliliers, G.L., Polli, E., Nappi, G., and Silani, V., Transplantation of undifferentiated human mesenchymal stem cells protects against 6-hydroxydopamine neurotoxicity in the rat, Cell Transplant., 2010, vol. 19, pp. 203–217.
Blondheim, N., Levy, Y., Ben-Zur, T., Burshtein, A., Cherlow, T., Kan, I., Barsilai, R., Bahat-Stromza, M., Barhum, Y., Bulvik, S., Melamed, E., and Offen, D., Human mesenchymal stem cells express neural genes, suggesting a neural predisposition, Stem Cells Dev., 2006, vol. 15, pp. 141–164.
Borlongan, C.V., Kaneko, Y., Maki, M., Yu, S.J., Ali, M., Allickson, J.G., Sanberg, C.D., Kuzmin-Nichols, N., and Sanberg, P.R., Menstrual blood cells display stem cell-like phenotypic markers and exert neuroprotection following transplantation in experimental stroke, Stem Cells Dev., 2010, vol. 19, pp. 439–452.
Brohlin, M., Kingham, P., Novikova, L., Novikov, L., and Wiberg, M., Aging effect on neurotrophic activity of human mesenchymal stem cells, PLoS One, 2012, vol. 7, p. e45052.
Caplan, A.I., Mesenchymal stem cells, J. Orthop. Res., 1991, vol. 9, pp. 641–650.
Cho, N.H., Park, Y.K., Kim, Y.T., Yang, H., and Kim, S.K., Lifetime expression of stem cell markers in the uterine endometrium, Fertil. Steril., 2004, vol. 81, pp. 403–407.
Deng, J., Petersen, B.E., Steindler, D.A., Jorgensen, M.L., and Laywell, E.D., Mesenchymal stem cells spontaneously express neural proteins in culture and are neurogenic after transplantation, Stem Cells, 2006, vol. 24, pp. 1054–1064.
Friedenstein, A.J., Petrakova, K.V., Kurolesova, A.I., and Frolova, G.P., Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues, Transplantation, 1968, vol. 6, pp. 230–247.
Gargett, C.E., Identification and characterization of human endometrial stem/progenitor cells, Aust. NZ J. Obstet. Gynaecol., 2006, vol. 46, pp. 250–253.
Glavaski-Joksimovic, A., Virag, T., Mangatu, T.A., McGrogan, M., Wang, X.S., and Bohn, M.C., Glial cell line-derived neurotrophic factor-secreting genetically modified human bone marrow-derived mesenchymal stem cells promote recovery in a rat model of Parkinson’s disease, J. Neurosci. Res., 2010, vol. 88, no. 12, pp. 2669–2681.
Gronthos, S., Franklin, D.M., Leddy, H.A., Robey, P.G., Storms, R.W., and Gimble, J.M., Surface protein characterization of human adipose tissue-derived stromal cells, J. Cell. Physiol., 2001, vol. 189, pp. 54–63.
Hass, R., Kasper, C., Bohm, S., and Jacobs, R., Different populations and sources of human mesenchymal stem cells (MSC): a comparison of adult and neonatal tissue-derived MSC, Cell Commun. Signal., 2011, vol. 9, pp. 12–23.
Hermann, A., Liebau, S., Gastl, R., Fickert, S., Habisch, H., Fiedler, J., Schwarz, J., Brenner, R., and Storch, A., Comparative analysis of neuroectodermal differentiation capacity of human bone marrow stromal cells using various conversion protocols, J. Neurosci. Res., 2006, vol. 83, pp. 1502–1514.
Kang, S.K., Lee, D.H., Bae, Y.C., Kim, H.K., Baik, S.Y., and Jung, J.S., Improvement of neurological deficits by intracerebral transplantation of human adipose tissue-derived stromal cells after cerebral ischemia in rats, Exp. Neurol., 2003, vol. 183, pp. 355–366.
Kearns, C.M. and Gash, D.M., GDNF protects nigral dopamine neurons against 6-hydroxydopamine in vivo, Brain Res., 1995, vol. 672, pp. 104–111.
Kim, B., Seo, J.H., Bubien, J.K., and Oh, Y.S., Differentiation of adult bone marrow stem cells into neuroprogenitor cells in vitro, Neuroreport, 2002, vol. 13, pp. 1185–1188.
Kim, H.J., Lee, J.H., and Ki, S.H., Therapeutic effects of human mesenchymal stem cells on traumatic brain injury in rats: secretion of neurotrophic factors and inhibition of apoptosis, J. Neurotrauma, 2010, vol. 27, pp. 131–138.
Kurozumi, K., Nakamura, K., Tamiya, T., Kawano, Y., Ishii, K., Kobune, M., Hirai, S., Uchida, H., Sasaki, K., Ito, Y., Kato, K., Honmou, O., Houkin, K., Date, I., and Hamada, H., Mesenchymal stem cells that produce neurotrophicfactors reduce ischemic damage in the rat middle cerebral artery occlusion model, Mol. Ther., 2005, vol. 11, pp. 96–104.
Li, Y., Chen, J., Chen, X.G., Wang, L., Gautam, S.C., Xu, Y.X., Katakowski, M., Zhang, L.J., Lu, M., Janakiraman, N., and Chopp, M., Human marrow stromal cell therapy for stroke in rat: neurotrophins and functional recovery, Neurology, 2002, vol. 59, pp. 514–523.
Lopatina, T.V., Kalinina, N.I., Revishchin, A.V., Beme, A.A., Spirova, I.A., Pavlova, G.V., and Parfenova, E.V., Induction of neural differentiation of adipose tissue stromal cells, Klet. Transplantol. Tkan. Inzhener., 2008, vol. 3, no. 4, pp. 50–55.
Lopatina, T., Kalinina, N., Karagyaur, M., Stambolsky, D., Rubina, K., Revischin, A., Pavlova, G., Parfyonova, Y., and Tcachuk, V., Adipose-derived stem cells stimulate regeneration of peripheral nerves: BDNF secreted by these cells promotes nerve healing and axon growth de novo, PLoS One, 2011, vol. 6, p. e17899.
McCoy, M.K., Martinez, T.N., Ruhn, K.A., Wrage, P.C., Keefer, E.W., Botterman, B.R., Tansey, K.E., and Tansey, M.G., Autologous transplants of adipose-derived adult stromal (ADAS) cells afford dopaminergic neuroprotection in a model of Parkinson’s disease, Exp. Neurol., 2008, vol. 210, pp. 14–29.
Meirelles, L.S., Fontes, A.M., Covas, D.T., and Caplan, A.I., Mechanisms involved in the therapeutic properties of mesenchymal stem cells, Cytokine Growth Factor Rev., 2009, vol. 20, pp. 419–427.
Meng, X., Ichim, T.E., Zhong, J., Rogers, A., Yin, Z., Jackson, J., Wang, H., Ge, W., Bogin, V., Chan, K.W., Thébaud, B., and Riordan, N.H., Endometrial regenerative cells: a novel stem cell population, J. Transl. Med., 2007, vol. 5, pp. 57–66.
Molero, A.E., Gokhan, S., Gonzalez, S., Feig, J.L., Alexandre, L.C., and Mehler, M.F., Impairment of developmental stem cell-mediated striatal neurogenesis and pluripotency genes in a knock-in model of Huntington’s disease, Proc. Natl. Acad. Sci. USA, 2009, vol. 106, pp. 21900–21905.
Moloney, T.C., Rooney, G.E., Barry, F.P., Howard, L., and Dowd, E., Potential of rat bone marrow-derived mesenchymal stem cells as vehicles for delivery of neurotrophins to the parkinsonian rat brain, Brain Res., 2010, vol. 1359, pp. 33–43.
Musina, R.A., Belyavski, A.V., Tarusova, O.V., Solovyova, E.V., and Sukhikh, G.T., Endometrial mesenchymal stem cells isolated from the menstrual blood, Bull. Exp. Biol. Med., 2008, vol. 145, no. 4, pp. 539–543.
Noureddini, M., Verdi, J., Mortazavi-Tabatabaei, S.A., Sharif, S., Azimi, A., Keyhanvar, P., and Shoae-Hassani, A., Human endometrial stem cell neurogenesis in response to NGF and BFGF, Cell Biol. Int., 2012, vol. 36, pp. 961–966.
Olson, S.D., Pollock, K., Kambal, A., Cary, W., Mitchell, G., Tempkin, J., Stewart, H., McGee, J., Bauer, G., Kim, H.S., Tempkin, T., Wheelock, V., Annett, G., Dunbar, G., and Nolta, J.A., Genetically engineered mesenchymal stem cells as a proposed therapeutic for Huntington disease, Mol. Neurobiol., 2012, vol. 45, pp. 87–98.
Park, H.J., Shin, J.Y., Lee, B.R., Kim, H.O., and Lee, P.H., Mesenchymal stem cells augment neurogenesis in the sub-ventricular zone and enhance differentiation of neural precursor cells into dopaminergic neurons in the substantia nigra of a parkinsonian model, Cell Transplant., 2012, vol. 21, pp. 1629–1640.
Patel, A.N., Park, E., Kuzman, M., Benetti, F., Silva, F.J., and Allickson, J.G., Multipotent menstrual blood stromal stem cells: isolation, characterization, and differentiation, Cell Transplant., 2008, vol. 17, pp. 303–311.
Paul, G. and Anisimov, S.V., The secretome of mesenchymal stem cells: potential implications for?neuroregeneration, Biochimie, 2013, vol. 95, pp. 2246–2256.
Pavon-Fuentes, N., Blanco-Lezcano, L., Martinez-Martin, L., Castillo-Diaz, L., de la Cuetara-Bernal, K., Garcia-Miniet, R., Lorigados-Pedre, L., Coro-Grave de Peralta, Y., Garcia-Varona, A.Y., Rosillo-Marti, J.C., and Macias-Gonzalez, R., Stromal cell transplant in the 6-OHDA lesion model, Rev. Neurol., 2004, vol. 39, pp. 326–334.
Pittenger, M.F., Mackay, A.M., Beck, S.C., Jaiswal, R.K., Douglas, R., Mosca, J.D., Moorman, M.A., Simonetti, D.W., Craig, S., and Marshak, D.R., Multilineage potential of adult human mesenchymal stem cells, Science, 1999, vol. 284, pp. 143–147.
Planat-Benard, V., Silvestre, J.S., Cousin, B., Andre, M., Nibbelink, M., Tamarat, R., Clergue, M., Manneville, C., Saillan-Barreau, C., Duriez, M., Tedgui, A., Levy, B., Penicaud, L., and Casteilla, L., Plasticity of human adipose lineage cells toward endothelial cells: physiological and therapeutic perspectives, Circulation, 2004, vol. 109, pp. 656–663.
Rangappa, S., Fen, C., Lee, E.H., Bongso, A., and Wei, E.S., Transformation of adult mesenchymal stem cells isolated from the fatty tissue into cardiomyocytes, Ann. Thorac. Surg., 2003, vol. 75, pp. 775–779.
Sadan, O., Eldad, Melamed, E., and Offen, D., Intrastriatal transplantation of neurotrophic factor-secreting human mesenchymal stem cells improves motor function and extends survival in R6/2 transgenic mouse model for Huntington’s disease, PLoS One, 2012, vol. 4, p. e4f7f6dc013d4e.
Safford, K.M., Hicok, K.C., Safford, S.D., Halvorsen, Y.D., Wilkison, W.O., Gimble, J.M., and Rice, H.E., Neurogenic differentiation of murine and human adipose-derived stromal cells, Biochem. Biophys. Res. Commun., 2002, vol. 294, pp. 371–379.
Sasaki, M., Radtke, C., Tan, A.M., Zhao, P., Hamada, H., Houkin, K., Honmou, O., and Kocsis, J.D., BDNF-hyper-secreting human mesenchymal stem cells promote functional recovery, axonal sprouting, and protection of corticospinal neurons after spinal cord injury, J. Neurosci., 2009, vol. 29, pp. 14932–14941.
Sauer, H., Fischer, W., Nikkhah, G., Wiegand, S.J., Brundin, P., Lindsay, R.M., and Bjorklund, A., Brain-derived neurotrophic factor enhances function rather than survival of intrastriatal dopamine cell-rich grafts, Brain Res., 1993, vol. 626, pp. 37–44.
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., 2011, vol. 6, pp. 82–92.
Si, Y.L., Zhao, Y.L., Hao, H.J., Fu, X.B., and Han, W.D., MSCs: biological characteristics, clinical applications and their outstanding concerns, Ageing Res. Rev., 2011, vol. 10, pp. 93–103.
Tondreau, T., Lagneaux, L., Dejeneffe, M., Massy, M., Mortier, C., Delforge, A., and Bron, D., Bone marrow-derived mesenchymal stem cells already express specific neural proteins before any differentiation, Differentiation, 2004, vol. 72, pp. 319–326.
Wakabayashi, K., Nagai, A., Sheikh, A.M., Shiota, Y., Narantuya, D., Watanabe, T., Masuda, J., Kobayashi, S., Kim, S.U., 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., 2010, vol. 88, pp. 1017–1025.
Wolff, E.F., Gao, X.B., Yao, K.V., Andrews, Z.B., Du, H., Elsworth, J.D., and Taylor, H.S., Endometrial stem cell transplantation restores dopamine production in a Parkinson’s disease model, J. Cell. Mol. Med., 2011, vol. 15, pp. 747–755.
Woodbury, D., Schwarz, E.J., Prockop, D.J., and Black, I.B., Adult rat and human bone marrow stromal cells differentiate into neurons, J. Neurosci. Res., 2000, vol. 61, pp. 364–370.
Wu, J., Yu, W., Chen, Y., Su, Y., Ding, Z., Ren, H., Jiang, Y., and Wang, J., Intrastriatal transplantation of GDNF-engineered BMSCs and its neuroprotection in lactacystin-induced Parkinsonian rat model, Neurochem. Res., 2010, vol. 35, pp. 495–502.
Ye, M., Wang, X.J., Zhang, Y.H., Lu, G.Q., Liang, L., Xu, J.Y., and Sheng-Di, C., Therapeutic effects of differentiated bone marrow stromal cell transplantation on rat models of Parkinson’s disease, Parkinsonism Relat. Disord., 2007, vol. 13, pp. 44–49.
Zemelko, V.I., Grinchuk, T.M., Domnina, A.P., Artzibasheva, I.V., Zenin, V.V., Kirsanov, A.A., Bichevaia, N.K., Korsak, V.S., and Nikolskiy, N.N., Multipotent mesenchymal stem cells of desquamated endometrium: isolation, characterization, and application as a feeder layer for maintenance of human embryonic stem cells, Cell Tissue Biol., 2012, vol. 6, no. 1, pp. 1–11.
Zemelko, V.I., Kozhucharova, I.B., Alekseenko, L.L., Domnina, A.P., Reshetnikova, G.F., Puzanov, M.V., Dmitrieva, R.I., Grinchuk, T.M., Nikolskiy, N.N., and Anisimov, S.V., Neurogenic potential of human mesenchymal stem cells isolated from bone marrow, adipose tissue and endometrium: a comparative study, Cell Tissue Biol., 2013, vol. 7, no. 3, pp. 235–244.
Zhang, R., Liu, Y., Yan, K., Chen, L., Chen, X.R., Li, P., Chen, F.F., and Jiang, X.D., Anti-inflammatory and immunomodulatory mechanisms of mesenchymal stem cell transplantation in experimental traumatic brain injury, J. Neuroinflamm., 2013, vol. 10, pp. 106–118.
Zigova, T., Pencea, V., Wiegand, S.J., and Luskin, M.B., Intraventricular administration of BDNF increases the number of newly generated neurons in the adult olfactory bulb, Mol. Cell. Neurosci., 1998, vol. 11, pp. 234–245.
Zuk, P.A., Zhu, M., Ashjian, P., De Ugarte, D.A., Huang, J.A., Mizuno, H., Alfonso, Z.C., Fraser, J.K., Benhaim, P., and Hedrick, M.H., Human adipose tissue is a source of multipotent stem cells, Mol. Biol. Cell., 2002, vol. 13, pp. 4279–4295.
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Original Russian Text © V.I. Zemelko, I.V. Kozhucharova, Z.V. Kovaleva, A.P. Domnina, N.A. Pugovkina, I.I. Fridlyanskaya, M.V. Puzanov, S.V. Anisimov, T.M. Grinchuk, N.N. Nikolsky, 2014, published in Tsitologiya, 2014, Vol. 56, No. 3, pp. 204–211.
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Zemelko, V.I., Kozhucharova, I.V., Kovaleva, Z.V. et al. Brain-derived neurotrofic factor (BDNF) secretion of human mesenchymal stem cells isolated from bone marrow, endometrium and adipose tissue. Cell Tiss. Biol. 8, 283–291 (2014). https://doi.org/10.1134/S1990519X14040129
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DOI: https://doi.org/10.1134/S1990519X14040129