Jump to ContentJump to Main Navigation
Show Summary Details

Cellular and Molecular Biology Letters

Editor-in-Chief: /


IMPACT FACTOR increased in 2015: 1.753

SCImago Journal Rank (SJR) 2015: 0.788
Source Normalized Impact per Paper (SNIP) 2015: 0.645
Impact per Publication (IPP) 2015: 1.748

Online
ISSN
1689-1392
See all formats and pricing



Select Volume and Issue

Human mesenchymal stem cells express neuronal markers after osteogenic and adipogenic differentiation

183University of Milano-Bicocca

283Università degli Studi di Milano-Bicocca

© 2013 Versita Warsaw. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License. (CC BY-NC-ND 3.0)

Citation Information: Cellular and Molecular Biology Letters. Volume 18, Issue 2, Pages 163–186, ISSN (Online) 1689-1392, DOI: https://doi.org/10.2478/s11658-013-0083-2, May 2013

Publication History

Published Online:
2013-05-11

Abstract

Mesenchymal stem cells (MSCs) are multipotent cells that are able to differentiate into mesodermal lineages (osteogenic, adipogenic, chondrogenic), but also towards non-mesodermal derivatives (e.g. neural cells). Recent in vitro studies revealed that, in the absence of any kind of differentiation stimuli, undifferentiated MSCs express neural differentiation markers, but the literature data do not all concur. Considering their promising therapeutic potential for neurodegenerative diseases, it is very important to expand our knowledge about this particular biological property of MSCs. In this study, we confirmed the spontaneous expression of neural markers (neuronal, glial and progenitor markers) by undifferentiated human MSCs (hMSCs) and in particular, we demonstrated that the neuronal markers βIII-tubulin and NeuN are expressed by a very high percentage of hMSCs, regardless of the number of culture passages and the culture conditions. Moreover, the neuronal markers βIII-tubulin and NeuN are still expressed by hMSCs after in vitro osteogenic and adipogenic differentiation. On the other hand, chondrogenically differentiated hMSCs are negative for these markers. Our findings suggest that the expression of neuronal markers could be common to a wide range of cellular types and not exclusive for neuronal lineages. Therefore, the expression of neuronal markers alone is not sufficient to demonstrate the differentiation of MSCs towards the neuronal phenotype. Functional properties analysis is also required.

Keywords: Mesenchymal stem cells; Neural markers; βIII-tubulin; NeuN; Osteogenic differentiation; Adipogenic differentiation; Chondrogenic differentiation; Neuronal differentiation

  • [1] 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 72 (2004) 319–326. http://dx.doi.org/10.1111/j.1432-0436.2004.07207003.x [Crossref]

  • [2] Minguell, J.J., Fierro, F.A., Epuñan, M.J., Erices, A.A., Sierralta and W.D. Nonstimulated human uncommitted mesenchymal stem cells express cell markers of mesenchymal and neural lineages. Stem Cells Dev. 14 (2005) 408–414. http://dx.doi.org/10.1089/scd.2005.14.408 [Crossref]

  • [3] Bertani, N., Malatesta, P., Volpi, G., Sonego, P. and Perris, R. Neurogenic potential of human mesenchymal stem cells revisited: analysis by immunostaining, time-lapse video and microarray. J. Cell. Sci. 118 (2005) 3925–3936. http://dx.doi.org/10.1242/jcs.02511 [Crossref]

  • [4] Blondheim, N.R., Levy, Y.S., Ben-Zur, T., Burshtein, A., Cherlow, T., Kan, I., Barzilai, 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. 15 (2006) 141–164. http://dx.doi.org/10.1089/scd.2006.15.141 [Crossref]

  • [5] Lamoury, F.M., Croitoru-Lamoury, J. and Brew, B.J. Undifferentiated mouse mesenchymal stem cells spontaneously express neural and stem cell markers Oct-4 and Rex-1. Cytotherapy 8 (2006) 228–242. http://dx.doi.org/10.1080/14653240600735875 [Crossref]

  • [6] Kamishina, H., Deng, J., Oji, T., Cheeseman, J.A. and Clemmons, R.M. Expression of neural markers on bone marrow-derived canine mesenchymal stem cells. Am. J. Vet. Res. 67 (2006) 1921–1928. http://dx.doi.org/10.2460/ajvr.67.11.1921 [Crossref]

  • [7] 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 (2011) 82–92. http://dx.doi.org/10.2174/157488811795495486 [Crossref]

  • [8] Scuteri, A., Ravasi, M., Pasini, S., Bossi, M. and Tredici, G. Mesenchymal stem cells support dorsal root ganglion neurons survival by inhibiting the metalloproteinase pathway. Neuroscience 172 (2011) 12–19. http://dx.doi.org/10.1016/j.neuroscience.2010.10.065 [Crossref]

  • [9] Salvadè, A., Belotti, D., Donzelli, E., D’Amico, G., Gaipa, G., Renoldi, G., Carini, F., Baldoni, M., Pogliani, E.M., Tredici, G., Biondi, A. and Biagi, E. GMP-grade preparation of biomimetic scaffolds with osteo-differentiated autologous mesenchymal stromal cells for the treatment of alveolar bone resorption in periodontal disease. Cytotherapy 9 (2007) 427–438. http://dx.doi.org/10.1080/14653240701341995 [Crossref]

  • [10] Tondreau, T., Dejeneffe, M., Meuleman, N., Stamatopoulos, B., Delforge, A., Martiat, P., Bron, D. and Lagneaux, L. Gene expression pattern of functional neuronal cells derived from human bone marrow mesenchymal stromal cells. BMC Genomics 9 (2008) 166. http://dx.doi.org/10.1186/1471-2164-9-166 [Crossref]

  • [11] Nicolini, G., Rigolio, R., Scuteri, A., Miloso, M., Saccomanno, D., Cavaletti, G. and Tredici, G. Effect of trans-resveratrol on signal transduction pathways involved in paclitaxel-induced apoptosis in human neuroblastoma SH-SY5Y cells. Neurochem. Int. 42 (2003) 419–429. http://dx.doi.org/10.1016/S0197-0186(02)00132-8

  • [12] Ronca, F., Chan, S.L. and Yu, V.C. 1-(5-Isoquinolinesulfonyl)-2-methylpiperazine induces apoptosis in human neuroblastoma cells, SH-SY5Y, through a p53-dependent pathway. J. Biol. Chem. 272 (1997) 4252–4260. http://dx.doi.org/10.1074/jbc.272.7.4252

  • [13] Dominici, M., Le Blanc, K., Mueller, I., Slaper-Cortenbach, I., Marini, F., Krause, D., Deans, R., Keating, A., Prockop, D.J. and Horwitz, E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8 (2006) 315–317. http://dx.doi.org/10.1080/14653240600855905 [Crossref]

  • [14] Redaelli, S., Bentivegna, A., Foudah, D., Miloso, M., Redondo, J., Riva, G., Baronchelli, L., Dalprà, L. and Tredici, G. From cytogenomic to epigenomic profiles: monitoring the biological behavior of in vitro cultured human bone marrow mesenchymal stem cells. Stem Cell Res. Ther. (2012) doi:10.1186/scrt138. [Crossref]

  • [15] Wiese, C., Rolletschek, A., Kania, G., Blyszczuk, P., Tarasov, K.V., Tarasova, Y., Wersto, R.P., Boheler, K.R. and Wobus, A.M. Nestin expression-a property of multi-lineage progenitor cells? Cell. Mol. Life Sci. 61 (2004) 2510–2522. http://dx.doi.org/10.1007/s00018-004-4144-6 [Crossref]

  • [16] Katsetos, C.D., Legido, A., Perentes, E. and Mörk, S.J. Class III beta-tubulin isotype: a key cytoskeletal protein at the crossroads of developmental neurobiology and tumor neuropathology. J. Child. Neurol. 18 (2003) 851–866. http://dx.doi.org/10.1177/088307380301801205 [Crossref]

  • [17] Mullen, R.J., Buck, C.R. and Smith, A.M. NeuN, a neuronal specific nuclear protein in vertebrates. Development 116 (1992) 201–211.

  • [18] Lee, M.K. and Cleveland, D.W. Neuronal intermediate filaments. Annu. Rev. Neurosci. 19 (1996) 187–217. http://dx.doi.org/10.1146/annurev.ne.19.030196.001155 [Crossref]

  • [19] Eng, L.F., Ghirnikar, R.S. and Lee, Y.L. Glial fibrillary acidic protein: GFAP-thirty-one years (1969–2000). Neurochem. Res. 25 (2000) 1439–1451. http://dx.doi.org/10.1023/A:1007677003387 [Crossref]

  • [20] Donato, R. S100: a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles. Int. J. Biochem. Cell. Biol. 33 (2001) 637–668. http://dx.doi.org/10.1016/S1357-2725(01)00046-2 [Crossref]

  • [21] Sodek, J., Ganss, B. and McKee, M.D. Osteopontin. Crit. Rev. Oral Biol. Med. 11 (2000) 279–303. http://dx.doi.org/10.1177/10454411000110030101 [Crossref]

  • [22] Hauschka, P.V. Osteocalcin: the vitamin K-dependent Ca2+-binding protein of bone matrix. Haemostasis 16 (1986) 258–272.

  • [23] Rosen, E.D. and Spiegelman, B.M. PPARgamma: a nuclear regulator of metabolism, differentiation, and cell growth. J. Biol. Chem. 276 (2001) 37731–37734. http://dx.doi.org/10.1074/jbc.M106424200 [Crossref]

  • [24] Dredge, B.K. and Jensen, K.B. NeuN/Rbfox3 nuclear and cytoplasmic isoforms differentially regulate alternative splicing and nonsense-mediated decay of Rbfox2. PLoS One 6 (2011) e21585. http://dx.doi.org/10.1371/journal.pone.0021585 [Crossref]

  • [25] Takashima, Y., Era, T., Nakao, K., Kondo, S., Kasuga, M., Smith, A.G. and Nishikawa, S. Neuroepithelial cells supply an initial transient wave of MSC differentiation. Cell 129 (2007) 1377–1388. http://dx.doi.org/10.1016/j.cell.2007.04.028 [Crossref]

  • [26] Nagoshi, N., Shibata, S., Kubota, Y., Nakamura, M., Nagai, Y., Satoh, E., Morikawa, S., Okada, Y., Mabuchi, Y., Katoh, H., Okada, S., Fukuda, K., Suda, T., Matsuzaki, Y., Toyama, Y. and Okano, H. Ontogeny and multipotency of neural crest-derived stem cells in mouse bone marrow, dorsal root ganglia, and whisker pad. Stem Cell 2 (2008) 392–403.

  • [27] Morikawa, S., Mabuchi, Y., Niibe, K., Suzuki, S., Nagoshi, N., Sunabori, T., Shimmura, S., Nagai, Y., Nakagawa, T., Okano, H. and Matsuzaki, Y. Development of mesenchymal stem cells partially originate from the neural crest. Biochem. Biophys. Res. Commun. 379 (2009) 1114–1119. http://dx.doi.org/10.1016/j.bbrc.2009.01.031 [Crossref]

  • [28] Croft, A.P. and Przyborski, S.A. Formation of neurons by non-neural adult stem cells: potential mechanism implicates an artifact of growth in culture. Stem Cells 24 (2006) 1841–1851. http://dx.doi.org/10.1634/stemcells.2005-0609 [Crossref]

  • [29] Barnabé, G.F., Schwindt, T.T., Calcagnotto, M.E., Motta, F.L., Martinez, G. Jr, de Oliveira, A.C. Keim, L.M., D’Almeida, V., Mendez-Otero, R. and Mello, L.E. Chemically-induced RAT mesenchymal stem cells adopt molecular properties of neuronal-like cells but do not have basic neuronal functional properties. PLoS One 4 (2009) e5222. http://dx.doi.org/10.1371/journal.pone.0005222 [Crossref]

  • [30] Schoenherr, C.J. and Anderson, D.J. The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes. Science 267 (1995) 1360–1363. http://dx.doi.org/10.1126/science.7871435 [Crossref]

  • [31] Gingras, M., Champigny, M.F. and Berthod, F. Differentiation of human adult skin-derived neuronal precursors into mature neurons. J. Cell. Physiol. 210 (2007) 498–506. http://dx.doi.org/10.1002/jcp.20889 [Crossref]

  • [32] Tischfield, M.A. and Engle, E.C. Distinct alpha- and beta-tubulin isotypes are required for the positioning, differentiation and survival of neurons: new support for the ‘multi-tubulin’ hypothesis. Biosci. Rep. 30 (2010) 319–330. http://dx.doi.org/10.1042/BSR20100025 [Crossref]

  • [33] Kim, K.K., Adelstein, R.S. and Kawamoto, S. Identification of neuronal nuclei (NeuN) as Fox-3, a new member of the Fox-1 gene family of splicing factors. J. Biol. Chem. 284 (2009) 31052–31061. http://dx.doi.org/10.1074/jbc.M109.052969 [Crossref]

  • [34] Dent, M.A., Segura-Anaya, E., Alva-Medina, J. and Aranda-Anzaldo, A. NeuN/Fox-3 is an intrinsic component of the neuronal nuclear matrix. FEBS Lett. 584 (2010) 2767–2771. http://dx.doi.org/10.1016/j.febslet.2010.04.073

  • [35] Beresford, J.N., Bennett, J.H., Devlin, C., Leboy, P. and Owen, M.E. Evidence for an inverse relationship between the differentiation of adipocytic and osteogenic cells in rat marrow stromal cell cultures. J. Cell. Sci. 102 (1992) 341–351.

  • [36] Park, S.R., Oreffo, R.O. and Triffitt, J.T. Interconversion potential of cloned human marrow adipocytes in vitro. Bone 24 (1999) 549–554. http://dx.doi.org/10.1016/S8756-3282(99)00084-8 [Crossref]

  • [37] Jaiswal, R.K., Jaiswal, N., Bruder, S.P., Mbalaviele, G., Marshak, D.R. and Pittenger, M.F. Adult human mesenchymal stem cell differentiation to the osteogenic or adipogenic lineage is regulated by mitogen-activated protein kinase. J. Biol. Chem. 275 (2000) 9645–9652. http://dx.doi.org/10.1074/jbc.275.13.9645 [Crossref]

  • [38] Muruganandan, S., Roman, A.A. and Sinal, C.J. Adipocyte differentiation of bone marrow-derived mesenchymal stem cells: cross talk with the osteoblastogenic program. Cell Mol. Life Sci. 66 (2009) 236–253. http://dx.doi.org/10.1007/s00018-008-8429-z [Crossref]

  • [39] Fu, L., Tang, T., Miao, Y., Zhang, S., Qu, Z. and Dai, K. Stimulation of osteogenic differentiation and inhibition of adipogenic differentiation in bone marrow stromal cells by alendronate via ERK and JNK activation. Bone 43 (2008) 40–47. http://dx.doi.org/10.1016/j.bone.2008.03.008 [Crossref]

  • [40] Santiago-Mora, R., Casado-Díaz, A., De Castro, M.D. and Quesada-Gómez, J.M. Oleuropein enhances osteoblastogenesis and inhibits adipogenesis: the effect on differentiation in stem cells derived from bone marrow. Osteoporos. Int. 22 (2011) 675–684. http://dx.doi.org/10.1007/s00198-010-1270-x [Crossref]

  • [41] Wang, L., Shao, Y.Y. and Ballock, R.T. Peroxisome proliferation-activated receptor-? promotes adipogenic changes in growth plate chondrocytes in vitro. PPAR Res. 2006 (2006) 67297. http://dx.doi.org/10.1155/PPAR/2006/67297 [Crossref]

  • [42] Lee, S., Choi, K., Ahn, H., Song, K., Choe, J. and Lee, I. TuJ1 (class III beta-tubulin) expression suggests dynamic redistribution of follicular dendritic cells in lymphoid tissue. Eur. J. Cell Biol. 84 (2005) 453–459. http://dx.doi.org/10.1016/j.ejcb.2004.11.001 [Crossref]

  • [43] Katsetos, C.D., Herman, M.M. and Mörk, S.J. Class III beta-tubulin in human development and cancer. Cell. Motil. Cytoskeleton 55 (2003) 77–96. http://dx.doi.org/10.1002/cm.10116 [Crossref]

  • [44] Ferrandina, G., Zannoni, G.F., Martinelli, E., Paglia, A., Gallotta, V., Mozzetti, S., Scambia, G. and Ferlini, C. Class III beta-tubulin overexpression is a marker of poor clinical outcome in advanced ovarian cancer patients. Clin. Cancer Res. 12 (2006) 2774–2779. http://dx.doi.org/10.1158/1078-0432.CCR-05-2715 [Crossref]

  • [45] Jouhilahti, E.M., Peltonen, S. and Peltonen, J. Class III beta-tubulin is a component of the mitotic spindle in multiple cell types. J. Histochem. Cytochem. 56 (2008) 1113–1119. http://dx.doi.org/10.1369/jhc.2008.952002 [Crossref]

  • [46] Gilyarov AV. Nestin in central nervous system cells. Neurosci. Behav. Physiol. 38 (2008) 165–169. http://dx.doi.org/10.1007/s11055-008-0025-z [Crossref]

  • [47] Kishaba, Y., Matsubara, D. and Niki, T. Heterogeneous expression of nestin in myofibroblasts of various human tissues. Pathol. Int. 60 (2010) 378–385. http://dx.doi.org/10.1111/j.1440-1827.2010.02532.x [Crossref]

  • [48] Krupkova, O. Jr, Loja, T., Zambo, I. and Veselska, R. Nestin expression in human tumors and tumor cell lines. Neoplasma 57 (2010) 291–298. http://dx.doi.org/10.4149/neo_2010_04_291 [Crossref]

  • [49] Piras, F., Perra, M.T., Murtas, D., Minerba, L., Floris, C., Maxia, C., Demurtas, P., Ugalde, J., Ribatti, D. and Sirigu, P. The stem cell marker nestin predicts poor prognosis in human melanoma. Oncol. Rep. 23 (2010) 17–24.

  • [50] Viale, G., Gambacorta, M., Coggi, G., Dell’Orto, P., Milani, M. and Doglioni, C. Glial fibrillary acidic protein immunoreactivity in normal and diseased human breast. Virchows Arch. A Pathol. Anat. Histopathol. 418 (1991) 339–348. http://dx.doi.org/10.1007/BF01600164 [Crossref]

  • [51] Salama, I., Malone, P.S., Mihaimeed, F. and Jones, J.L. A review of the S100 proteins in cancer. Eur. J. Surg. Oncol. 34 (2008) 357–364. http://dx.doi.org/10.1016/j.ejso.2007.04.009 [Crossref]

  • [52] Ichikawa, H., Itota, T., Torii, Y., Inoue, K. and Sugimoto, T. Osteocalcinimmunoreactive primary sensory neurons in the rat spinal and trigeminal nervous systems. Brain Res. 838 (1999) 205–209. http://dx.doi.org/10.1016/S0006-8993(99)01710-2 [Crossref]

  • [53] Sarruf, D.A., Yu, F., Nguyen, H.T., Williams, D.L., Printz, R.L., Niswender, K.D. and Schwartz, M.W. Expression of peroxisome proliferator-activated receptor-gamma in key neuronal subsets regulating glucose metabolism and energy homeostasis. Endocrinology 150 (2009) 707–712. http://dx.doi.org/10.1210/en.2008-0899 [Crossref]

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

[2]
Ping Yu, Elizabeth C. McKinney, Muthugapatti M. Kandasamy, Alexandria L. Albert, and Richard B. Meagher
Developmental Neurobiology, 2015, Volume 75, Number 7, Page 738
[3]
Peter C. Stapor, Richard S. Sweat, Derek C. Dashti, Aline M. Betancourt, and Walter Lee Murfee
Journal of Vascular Research, 2014, Volume 51, Number 3, Page 163
[4]
Molly R. Kelly-Goss, Rick S. Sweat, Peter C. Stapor, Shayn M. Peirce, and Walter L. Murfee
Microcirculation, 2014, Volume 21, Number 4, Page 345

Comments (0)

Please log in or register to comment.