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on Neurogenesis from Adult Human Mesenchymal Stem Cells: Implication for Inflammatory Mediators in Regenerative Medicine1
* Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103; and
Department of Medicine, University of Medicine and Dentistry of New Jersey–New Jersey Medical School, Newark, NJ 07103
Mesenchymal stem cells (MSCs) are mesoderm-derived cells, primarily resident in adult bone marrow. MSCs show lineage specificity in generating specialized cells such as stroma, fat, and cartilage. MSCs express MHC class II and function as phagocytes and APCs. Despite these immune-enhancing properties, MSCs also exert veto functions and show evidence for allogeneic transplantation. These properties, combined with ease in isolation and expansion, demonstrate MSCs as attractive candidates for tissue repair across allogeneic barriers. MSCs have also been shown to transdifferentiate in neuronal cells. We have reported expression of the neurotransmitter gene, Tac1, in MSC-derived neuronal cells, with no evidence of translation unless cells were stimulated with IL-1
. This result led us to question the potential role of immune mediators in the field of stem cell therapy. Using Tac1 as an experimental model, IL-1 was used as a prototypical inflammatory mediator to study functions on MSC-derived neuronal cells. Undifferentiated MSCs and those induced to form neurons were studied for their response to IL-1 and other proinflammatory cytokines using production of the major Tac1 peptide, substance P (SP), as readout. Although IL-1 induced high production of SP, a similar effect was not observed for all tested cytokines. The induced SP was capable of reuptake via its high-affinity NK1R and was found to stabilize IL-1R mRNA. IL-1 also enhanced the rate of neurogenesis, based on expression of neuronal markers and cRNA microarray analyses. The results provide evidence that inflammatory mediators need to be considered when deciding the course of MSC transplantation.
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1 This work was supported by a grant from the F. M. Kirby Foundation. This work was performed in partial fulfillment of a Ph.D. thesis by S.J.G. and was done at the Department of Medicine, Division of Hematology/Oncology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School (Newark, NJ).
2 Address correspondence and reprint requests to Dr. Pranela Rameshwar, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Medical Sciences Building, Room E-579, 185 South Orange Avenue, Newark, NJ 07103. E-mail address: rameshwa{at}umdnj.edu
3 Abbreviations used in this paper: ASC, adult stem cell; MSC, mesenchymal stem cell; BM, bone marrow; SP, substance P; hMSC, human MSC; DAPI, 4',6-diamidino-2-phenylindole, dilactate; NIM, neuronal induction medium; fSP, FITC-conjugated SP; miRNA, microRNA; MHC-II, MHC class II; RA, retinoic acid.
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  B. Y. Reddy, S. J. Greco, P. S. Patel, K. A. Trzaska, and P. Rameshwar RE-1-silencing transcription factor shows tumor-suppressor functions and negatively regulates the oncogenic TAC1 in breast cancer cells PNAS, March 17, 2009; 106(11): 4408 - 4413. [Abstract] [Full Text] [PDF]
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S. J. Greco and P. Rameshwar MicroRNAs regulate synthesis of the neurotransmitter substance P in human mesenchymal stem cell-derived neuronal cells PNAS, September 25, 2007; 104(39): 15484 - 15489. [Abstract] [Full Text] [PDF]
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