Abstract
Stem cell therapy is one of the most promising treatments in neuroregenerative medicine. Considering the role of the endogenous opioid system in controlling the pathophysiology of neurological disorders and behavioral aberrations, current studies have focused on enkephalins as a part of the opioid system. Due to high capability of unrestricted somatic stem cells (USSCs) and human mesenchymal stem cells (hMSCs) for cell therapy and transplantation; here, we examined their enkephalinergic differentiation potential through Ikaros-related pathways in order to develop in vitro models to help drug screening and stem cell therapy for the opioid-related disorders. The authenticity of the stem cells was verified by differentiation experiments along with flow cytometry for surface markers. Later, we confirmed their neurogenic differentiation with semiquantitative and quantitative transcriptional and translational evaluations of the enkephalinergic-related genes such as proenkephalin, CREBZF, Ikaros, and prodynorphin. Our findings supported the enkephalinergic differentiation of these stem cells. Noteworthy, USSCs showed higher potential for differentiating into enkephalinergic neurons under Ikaros activation than hMSCs, which makes them appropriate for neurological therapeutic applications. In conclusion, this study suggests a powerful in vitro model for neurogenesis that may help clarification of enkephalinergic differentiation and related signaling networks along with neural drug screening. Such investigations may be beneficial to ameliorate the neural-related therapeutic approaches.
Similar content being viewed by others
References
A A, V T, T T, D DS, E P, G D, G M. Performance Analysis in Sabre. J Strength Cond Res; 2012.
Abdel-Salam O. M. Stem cell therapy for Alzheimer’s disease. CNS Neurol Disord Drug Targets 10: 459–485; 2011.
Agoston D. V.; Szemes M.; Dobi A.; Palkovits M.; Georgopoulos K.; Gyorgy A.; Ring M. A. Ikaros is expressed in developing striatal neurons and involved in enkephalinergic differentiation. J Neurochem 102: 1805–1816; 2007.
Arora T.; Mehta A. K.; Joshi V.; Mehta K. D.; Rathor N.; Mediratta P. K.; Sharma K. K. Substitute of animals in drug research: an approach towards fulfillment of 4R’s. Indian J Pharm Sci 73: 1–6; 2011.
Bakhshandeh B.; Soleimani M.; Hafizi M.; Ghaemi N. A comparative study on nonviral genetic modifications in cord blood and bone marrow mesenchymal stem cells. Cytotechnology 64(5): 523–540; 2012a.
Bakhshandeh B.; Soleimani M.; Hafizi M.; Paylakhi S. H.; Ghaemi N. MicroRNA signature associated with osteogenic lineage commitment. Mol Biol Rep 39(7): 7569–7581; 2012b.
Bremer S.; Hartung T. The use of embryonic stem cells for regulatory developmental toxicity testing in vitro–the current status of test development. Curr Pharm Des 10: 2733–2747; 2004.
Charbord P. Bone marrow mesenchymal stem cells: historical overview and concepts. Hum Gene Ther 21: 1045–1056; 2010.
Chavkin C.; Shoemaker W. J.; McGinty J. F.; Bayon A.; Bloom F. E. Characterization of the prodynorphin and proenkephalin neuropeptide systems in rat hippocampus. J Neurosci 5: 808–816; 1985.
Dvorakova J.; Hruba A.; Velebny V.; Kubala L. Isolation and characterization of mesenchymal stem cell population entrapped in bone marrow collection sets. Cell Biol Int 32: 1116–1125; 2008.
Fallahi-Sichani M.; Soleimani M.; Najafi S. M.; Kiani J.; Arefian E.; Atashi A. In vitro differentiation of cord blood unrestricted somatic stem cells expressing dopamine-associated genes into neuron-like cells. Cell Biol Int 31: 299–303; 2007.
Gurling H. Candidate genes and favoured loci: strategies for molecular genetic research into schizophrenia, manic depression, autism, alcoholism and Alzheimer’s disease. Psychiatr Dev 4: 289–309; 1986.
Hao L.; Sun H.; Wang J.; Wang T.; Wang M.; Zou Z. Mesenchymal stromal cells for cell therapy: besides supporting hematopoiesis. Int J Hematol 95(1): 34–46; 2011.
Ichim T. E.; Solano F.; Glenn E.; Morales F.; Smith L.; Zabrecky G.; Riordan N. H. Stem cell therapy for autism. J Transl Med 5: 30; 2007.
Israngkun P. P.; Newman H. A.; Patel S. T.; Duruibe V. A.; Abou-Issa H. Potential biochemical markers for infantile autism. Neurochem Pathol 5: 51–70; 1986.
Kern S.; Eichler H.; Stoeve J.; Kluter H.; Bieback K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells 24: 1294–1301; 2006.
Kidd P. M. Autism, an extreme challenge to integrative medicine. Part: 1: the knowledge base. Altern Med Rev 7: 292–316; 2002.
Kim S. W.; Han H.; Chae G. T.; Lee S. H.; Bo S.; Yoon J. H.; Lee Y. S.; Lee K. S.; Park H. K.; Kang K. S. Successful stem cell therapy using umbilical cord blood-derived multipotent stem cells for Buerger’s disease and ischemic limb disease animal model. Stem Cells 24: 1620–1626; 2006.
Kogler G.; Sensken S.; Airey J. A.; Trapp T.; Muschen M.; Feldhahn N.; Liedtke S.; Sorg R. V.; Fischer J.; Rosenbaum C.; Greschat S.; Knipper A.; Bender J.; Degistirici O.; Gao J.; Caplan A. I.; Colletti E. J.; Almeida-Porada G.; Muller H. W.; Zanjani E.; Wernet P. A new human somatic stem cell from placental cord blood with intrinsic pluripotent differentiation potential. J Exp Med 200: 123–135; 2004.
Le Merrer J.; Becker J. A.; Befort K.; Kieffer B. L. Reward processing by the opioid system in the brain. Physiol Rev 89: 1379–1412; 2009.
Lunn J. S.; Sakowski S. A.; Hur J.; Feldman E. L. Stem cell technology for neurodegenerative diseases. Ann Neurol 70: 353–361; 2011.
Martin-Ibanez R.; Crespo E.; Urban N.; Sergent-Tanguy S.; Herranz C.; Jaumot M.; Valiente M.; Long J. E.; Pineda J. R.; Andreu C.; Rubenstein J. L.; Marin O.; Georgopoulos K.; Mengod G.; Farinas I.; Bachs O.; Alberch J.; Canals J. M. Ikaros-1 couples cell cycle arrest of late striatal precursors with neurogenesis of enkephalinergic neurons. J Comp Neurol 518: 329–351; 2010.
Nandhu M. S.; Naijil G.; Smijin S.; Jayanarayanan S.; Paulose C. S. Opioid system functional regulation in neurological disease management. J Neurosci Res 88: 3215–3221; 2010.
Nichogiannopoulou A.; Trevisan M.; Friedrich C.; Georgopoulos K. Ikaros in hemopoietic lineage determination and homeostasis. Semin Immunol 10: 119–125; 1998.
Oltean S.; Tulescu D. T.; Bondor C.; Slavcovici A.; Cismaru C.; Lupse M.; Muntean M.; Jianu C.; Marcu C.; Oltean M. Charlson’s weighted index of comorbidities is useful in assessing the risk of death in septic patients. J Crit Care 27: 370–375; 2012.
Palmer T. D.; Schwartz P. H.; Taupin P.; Kaspar B.; Stein S. A.; Gage F. H. Cell culture. Progenitor cells from human brain after death. Nature 411: 42–43; 2001.
Perez-Rosado A.; Gomez M.; Manzanares J.; Ramos J. A.; Fernandez-Ruiz J. Changes in prodynorphin and POMC gene expression in several brain regions of rat fetuses prenatally exposed to Delta(9)-tetrahydrocannabinol. Neurotox Res 4: 211–218; 2002.
Previc F. H. Prenatal influences on brain dopamine and their relevance to the rising incidence of autism. Med Hypotheses 68: 46–60; 2007.
Sadan O.; Melamed E.; Offen D. Bone-marrow-derived mesenchymal stem cell therapy for neurodegenerative diseases. Expert Opin Biol Ther 9: 1487–1497; 2009.
Schneider T.; Ziolkowska B.; Gieryk A.; Tyminska A.; Przewlocki R. Prenatal exposure to valproic acid disturbs the enkephalinergic system functioning, basal hedonic tone, and emotional responses in an animal model of autism. Psychopharmacology (Berl) 193: 547–555; 2007.
Sensken S.; Waclawczyk S.; Knaupp A. S.; Trapp T.; Enczmann J.; Wernet P.; Kogler G. In vitro differentiation of human cord blood-derived unrestricted somatic stem cells towards an endodermal pathway. Cytotherapy 9: 362–378; 2007.
Shihabuddin L. S.; Aubert I. Stem cell transplantation for neurometabolic and neurodegenerative diseases. Neuropharmacology 58: 845–854; 2010.
Tanimura Y.; Vaziri S.; Lewis M. H. Indirect basal ganglia pathway mediation of repetitive behavior: attenuation by adenosine receptor agonists. Behav Brain Res 210: 116–122; 2010.
Tondreau T.; Dejeneffe M.; Meuleman N.; Stamatopoulos B.; Delforge A.; Martiat P.; Bron D.; Lagneaux L. Gene expression pattern of functional neuronal cells derived from human bone marrow mesenchymal stromal cells. BMC Genomics 9: 166; 2008.
Trzaska K. A.; Rameshwar P. Current advances in the treatment of Parkinson’s disease with stem cells. Curr Neurovasc Res 4: 99–109; 2007.
Vanegas H.; Tortorici V. Opioidergic effects of nonopioid analgesics on the central nervous system. Cell Mol Neurobiol 22: 655–661; 2002.
Yahata N.; Asai M.; Kitaoka S.; Takahashi K.; Asaka I.; Hioki H.; Kaneko T.; Maruyama K.; Saido T. C.; Nakahata T.; Asada T.; Yamanaka S.; Iwata N.; Inoue H. Anti-Abeta drug screening platform using human iPS cell-derived neurons for the treatment of Alzheimer’s disease. PLoS One 6: e25788; 2011.
Acknowledgments
This work was supported financially by Stem Cell Technology Research Center.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Editor: T. Okamoto
Behnaz Bakhshandeh and Maryam Hafizi contributed equally to this work.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Figure 1
Osteogenic (Alizarin Red), Adipogenic (Oil Red), and chondrogenic (Alcian Blue) differentiation of stem cells after 21 d of in vitro induction. Bars 100 μm (JPEG 75 kb)
Rights and permissions
About this article
Cite this article
Hafizi, M., Bakhshandeh, B., Soleimani, M. et al. Exploring the enkephalinergic differentiation potential in adult stem cells for cell therapy and drug screening implications. In Vitro Cell.Dev.Biol.-Animal 48, 562–569 (2012). https://doi.org/10.1007/s11626-012-9546-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11626-012-9546-4