Chemically primed bone-marrow derived mesenchymal stem cells show enhanced expression of chemokine receptors contributed to their migration capability

Document Type : Original Article

Authors

1 Department of Biology, Faculty of Sciences, Ferdowsi University of Mashhad, Mashhad, Iran

2 Stem Cells and Regenerative Medicine Research Department, ACECR-Khorasan Razavi Branch, Mashhad, Iran

3 Shahroud University of Medical Sciences, Shahroud, Iran

4 Molecular Medicine Research Department, ACECR-Khorasan Razavi Branch, Mashhad, Iran

5 Cell and Molecular Biotechnology Research group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran

Abstract

Objective(s):The limited homing potential of bone-marrow-derived mesenchymal stem cells (BM-MSC) is the key obstacle in MSC-based therapy. It is believed that chemokines and chemokine receptor interactions play key roles in cellular processes associated with migration. Meanwhile, MSCs express a low level of distinct chemokine receptors and they even lose these receptors on their surface after a few passages which influence their therapeutic applications negatively. This study investigated whether treatment of BM-MSCs with hypoxia-mimicking agents would increase expression of some chemokine receptors and cell migration.
Materials and Methods: BM-MSCs were treated at passage 2 for our gene expression profiling. All qPCR experiments were performed by SYBR Green method in CFX-96 Bio-Rad Real-Time PCR. The Boyden chamber assay was utilized to investigate BM-MSC homing.
Results:Possible approaches to increasing the expression level of chemokine receptors by different hypoxia-mimicking agents such as valproic acid (VPA), CoCl2, and desferrioxamine (DFX) are described. Results show DFX efficiently up-regulate the CXCR7 and CXCR4 gene expression while VPA increase only the CXCR7 gene expression and no significant change in expression level of CXCR4 and the CXCR7 gene was detectable by CoCl2 treatment. Chemotaxis assay results show that pre-treatment with DFX, VPA, and Cocl2 enhances significantly the migration ability of BM-MSCs compared with the untreated control group and DFX treatment accelerates MSCs homing significantly with a higher rate than VPA and Cocl2 treatments.
Conclusion: Our data supports the notion that pretreatment of MSC with VPA and DFX improves the efficiency of MSC therapy by triggering homing regulatory signaling pathways.

Keywords

References

1. Ankrum J, Karp JM. Mesenchymal stem cell therapy: Two steps forward, one step back. Trends  Mol Med 2010; 16:203-209.
2. Wynn RF, Hart CA, Corradi-Perini C, O'Neill L, Evans CA, Wraith JE, et al. A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow. Blood 2004; 104:2643-2645.
3. Liu H, Liu S, Li Y, Wang X, Xue W, Ge G, et al. The role of SDF-1-CXCR4/CXCR7 axis in the therapeutic effects of hypoxia-preconditioned mesenchymal stem cells for renal ischemia/reperfusion injury. PloS One 2012; 7:e34608.
4. Potapova IA, Brink PR, Cohen IS, Doronin SV. Culturing of human mesenchymal stem cells as three-dimensional aggregates induces functional expression of CXCR4 that regulates adhesion to endothelial cells. J Biol Chem 2008; 283:13100-13107.
5. Honczarenko M, Le Y, Swierkowski M, Ghiran I, Glodek AM, Silberstein LE. Human bone marrow stromal cells express a distinct set of biologically functional chemokine receptors. Stem Cells 2006; 24:1030-1041.
6. Naderi-Meshkin H, Matin MM, Heirani-Tabasi A, Mirahmadi M, Irfan-Maqsood M, Edalatmanesh MA, et al. Injectable hydrogel delivery plus preconditioning of mesenchymal stem cells: exploitation of SDF-1/CXCR4 axis towards enhancing the efficacy of stem cells' homing. Cell Biol Int 2015: doi: 10.1002/cbin.10474. [Epub ahead of print]
7. Naderi-Meshkin H, Bahrami AR, Bidkhori HR, Mirahmadi M, Ahmadiankia N. Strategies to improve homing of mesenchymal stem cells for greater efficacy in stem cell therapy. Cell Biol Int 2015; 39:23-34. 8. Tsai LK, Leng Y, Wang Z, Leeds P, Chuang DM. The mood stabilizers valproic acid and lithium enhance mesenchymal stem cell migration via distinct mechanisms. Neuropsychopharmacology 2010; 35:2225-2237.
9. Li L, Yin X, Ma N, Lin F, Kong X, Chi J, et al. Desferrioxamine regulates HIF-1 alpha expression in neonatal rat brain after hypoxia-ischemia. Am J Translat Res 2014; 6:377-383.
10. Pacary E, Legros H, Valable S, Duchatelle P, Lecocq M, Petit E, et al. Synergistic effects of CoCl(2) and ROCK inhibition on mesenchymal stem cell differentiation into neuron-like cells. J Cell Sci 2006; 119:2667-2678.
11. Koch-Weser J, Browne TR. Drug therapy: Valproic acid. N Engl J Med 1980; 302:661-666.
12. da Silva Meirelles L, Caplan AI, Nardi NB. In search of the in vivo identity of mesenchymal stem cells. Stem Cells 2008; 26:2287-2299.
13. Ahmadian Kia N, Bahrami AR, Ebrahimi M, Matin MM, Neshati Z, Almohaddesin MR, et al. Comparative analysis of chemokine receptor's expression in mesenchymal stem cells derived from human bone marrow and adipose tissue. J Mol Neurosci 2011; 44:178-185.
14. Ganju RK, Brubaker SA, Meyer J, Dutt P, Yang Y, Qin S, et al. The alpha-chemokine, stromal cell-derived factor-1alpha, binds to the transmembrane G-protein-coupled CXCR-4 receptor and activates multiple signal transduction pathways.  J Biol chem 1998; 273:23169-23175.
15. De Clercq E. The bicyclam AMD3100 story. Nat Rev Drug Discov 2003; 2:581-587.
16. Tsai LK, Wang Z, Munasinghe J, Leng Y, Leeds P, Chuang DM. Mesenchymal stem cells primed with valproate and lithium robustly migrate to infarcted regions and facilitate recovery in a stroke model. Stroke 2011; 42:2932-2939.
17. Jeon ES, Shin JH, Hwang SJ, Moon GJ, Bang OY, Kim HH. Cobalt chloride induces neuronal differentiation of human mesenchymal stem cells through upregulation of microRNA-124a. Biochem Biophys Res Commun 2014; 444:581-587.
18. McDermott DH, Lopez J, Deng F, Liu Q, Ojode T, Chen H, et al. AMD3100 is a potent antagonist at CXCR4(R334X) , a hyperfunctional mutant chemokine receptor and cause of WHIM syndrome. J Cell Mol Med 2011; 15:2071-2081.
19. Won YW, Patel AN, Bull DA. Cell surface engineering to enhance mesenchymal stem cell migration toward an SDF-1 gradient. Biomaterials 2014; 35):5627-5635.
20. Sarkar D, Zhao W, Gupta A, Loh WL, Karnik R, Karp JM. Cell surface engineering of mesenchymal stem cells. Methods Mol Biol 2011; 698:505-523.
21. Sarkar D, Spencer JA, Phillips JA, Zhao W, Schafer S, Spelke DP, et al. Engineered cell homing. Blood 2011; 118:e184-191.
22. Mazzinghi B, Ronconi E, Lazzeri E, Sagrinati C, Ballerini L, Angelotti ML, et al. Essential but differential role for CXCR4 and CXCR7 in the therapeutic homing of human renal progenitor cells. J Exp Med 2008; 205:479-490.
23.Najafi R, Sharifi AM. Deferoxamine preconditioning potentiates mesenchymal stem cell homing in vitro and in streptozotocin-diabetic rats. Expert Opin Biol Ther 2013; 13:959-972.
24. Zabel BA, Wang Y, Lewen S, Berahovich RD, Penfold ME, Zhang P, et al. Elucidation of CXCR7-mediated signaling events and inhibition of CXCR4-mediated tumor cell transendothelial migration by CXCR7 ligands. J Immunol 2009; 183:3204-3211.
25. Gul H, Marquez-Curtis LA, Jahroudi N, Larratt LM, Janowska-Wieczorek A. Valproic acid exerts differential effects on CXCR4 expression in leukemic cells. Leuk Res 2010; 34:235-242.
26. Cho GW, Kang BY, Kim KS, Kim SH. Effects of valproic acid on the expression of trophic factors in human bone marrow mesenchymal stromal cells. Neurosci Lett 2012; 526:100-105.
27. Jeong SG, Ohn T, Kim SH, Cho GW. Valproic acid promotes neuronal differentiation by induction of neuroprogenitors in human bone-marrow mesenchymal stromal cells. Neurosci Lett 2013; 554:22-27.

Files

Share

How to cite

Statistics