Skip to main content

Advertisement

SpringerLink
Log in

Comparison the effects of hypoxia-mimicking agents on migration-related signaling pathways in mesenchymal stem cells

  • Published:
Cell and Tissue Banking Aims and scope Submit manuscript

Abstract

Adipose-derived mesenchymal stem cells (Ad-MSCs) have been designated as the promising agents for clinical applications for easy accessibility, multi-linage differentiation and immunomodulation capacity. Despite this, optimal cell delivery conditions have remained as a clinical challenge and improvement of stem cell homing to the target organs is being considered as a major strategy in cell therapy systemic injection. It has been shown that homing of mesenchymal stem cells are increased when treated with physical or chemical hypoxia-mimicking factors, however, efficiency of different agents remained to be determined. In this study, hypoxia-mimicking agents, including valproic acid (VPA), cobalt chloride (CoCl2) and deferoxamine (DFX) were examined to determine whether they are able to activate signaling molecules involved in migration of Ad-MSCs in vitro. We report that Ad-MSCs treated by DFX resulted in a significantly enhanced mRNA expression of MAPK4 (associated with MAPK signaling pathway), INPP4B (associated with Inositol polyphosphate pathway), VEGF-A and VEGF-C (associated with cytokine–cytokine receptor pathways), IL-8 and its receptor, CXCR2 (associated with IL-8 signaling pathway). While the cells treated with VPA did not show such effects and CoCl2 only upregulated VEGF-A and VEGF-C gene expression. Furthermore, results of wound-healing assays showed migration capacity of Ad-MSCs treated with DFX significantly increased 8 and 24 h of the treatment. This study provides credible evidence around DFX, which might be an effective drug for pharmacological preconditioning of Ad-MSCs to boost their homing capacity and regeneration of damaged tissues though, activation of the migration-related signaling pathways.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Al-Sowayan B, Keogh RJ, Abumaree M, Georgiou HM, Kalionis B (2019) Valproic acid stimulates in vitro migration of the placenta-derived mesenchymal stem/stromal cell line CMSC29. Stem Cell Investig 6:3

    CAS  PubMed Central  Google Scholar 

  • Bancroft CC, Chen Z, Dong G, Sunwoo JB, Yeh N, Park C, Van Waes C (2001) Coexpression of proangiogenic factors IL-8 and VEGF by human head and neck squamous cell carcinoma involves coactivation by MEK-MAPK and IKK-NF-κB signal pathways. Clin Cancer Res 7:435–442

    CAS  Google Scholar 

  • Campbell M, Trimble ER (2005) Modification of PI3K-and MAPK-dependent chemotaxis in aortic vascular smooth muscle cells by protein kinase CβII. Circ Res 96:197–206

    CAS  Google Scholar 

  • Chen Y, Tsai Y-H, Tseng S-H (2012) Valproic acid affected the survival and invasiveness of human glioma cells through diverse mechanisms. J Neurooncol 109:23–33

    CAS  Google Scholar 

  • Chen L, Cui X, Wu Z, Jia L, Yu Y, Zhou Q et al (2014) Transplantation of bone marrow mesenchymal stem cells pretreated with valproic acid in rats with an acute spinal cord injury. Biosci Trends 8:111–119

    CAS  Google Scholar 

  • Deezagi A, Shomali S (2018) Prostaglandin F-2α stimulates the secretion of vascular endothelial growth factor and induces cell proliferation and migration of adipose tissue derived mesenchymal stem cells. Cell J 20:259–266

    PubMed Central  Google Scholar 

  • Fu X, Liu G, Halim A, Ju Y, Luo Q, Song G (2019) Mesenchymal stem cell migration and tissue repair. Cells 8:784

    CAS  Google Scholar 

  • Gasser JA, Inuzuka H, Lau AW, Wei W, Beroukhim R, Toker A (2014) SGK3 mediates INPP4B-dependent PI3K signaling in breast cancer. Mol Cell 56:595–607

    CAS  PubMed Central  Google Scholar 

  • Gimble JM, Katz AJ, Bunnell BA (2007) Adipose-derived stem cells for regenerative medicine. Circ Res 100:1249–1260

    CAS  PubMed Central  Google Scholar 

  • Guo M, Song L-P, Jiang Y, Liu W, Yu Y, Chen G-Q (2006) Hypoxia-mimetic agents desferrioxamine and cobalt chloride induce leukemic cell apoptosis through different hypoxia-inducible factor-1α independent mechanisms. Apoptosis 11:67–77

    CAS  Google Scholar 

  • Hashemzadeh MR, Seyedi Z, Rafiei S, Hassanzadeh-Moghaddam M, Edalatmanesh MA (2017) Chemokine receptor’s expression in human adipose derived mesenchymal stem cells primed with valproic acid. Comp Clin Path 26:115–120

    CAS  Google Scholar 

  • Heirani-Tabasi A, Toosi S, Mirahmadi M, Mishan MA, Bidkhori HR, Bahrami AR et al (2017) Chemokine receptors expression in MSCs: comparative analysis in different sources and passages. Tissue Eng Regen Med 14:605–615

    CAS  PubMed Central  Google Scholar 

  • Heirani-Tabasi A, Naderi-Meshkin H, Matin MM, Mirahmadi M, Shahriyari M, Ahmadiankia N et al (2018) Augmented migration of mesenchymal stem cells correlates with the subsidiary CXCR4 variant. Cell Adh Migr 12:118–126

    CAS  PubMed Central  Google Scholar 

  • Hu C, Zhao L, Li L (2019) Current understanding of adipose-derived mesenchymal stem cell-based therapies in liver diseases. Stem Cell Res Ther 10:199

    PubMed Central  Google Scholar 

  • Hung S-C, Pochampally RR, Hsu S-C, Sanchez C, Chen S-C, Spees J, Prockop DJ (2007) Short-term exposure of multipotent stromal cells to low oxygen increases their expression of CX3CR1 and CXCR4 and their engraftment in vivo. PloS ONE 2:e416

    PubMed Central  Google Scholar 

  • Jeong H-J, Chung H-S, Lee B-R, Kim S-J, Yoo S-J, Hong S-H, Kim H-M (2003) Expression of proinflammatory cytokines via HIF-1α and NF-κB activation on desferrioxamine-stimulated HMC-1 cells. Biochem Biophys Res Commun 306:805–811

    CAS  Google Scholar 

  • Kuhbier JW, Weyand B, Radtke C, Vogt PM, Kasper C, Reimers K (2010) Isolation, characterization, differentiation, and application of adipose-derived stem cells. Adv Biochem Eng Biotechnol 123:55–105

    CAS  Google Scholar 

  • Lee H-J, Lee J, Lee S-K, Lee S-K, Kim E-C (2007) Differential regulation of iron chelator-induced IL-8 synthesis via MAP kinase and NF-κB in immortalized and malignant oral keratinocytes. BMC Cancer 7:176

    PubMed Central  Google Scholar 

  • Li A, Dubey S, Varney ML, Dave BJ, Singh RK (2003) IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis. J Immunol 170:3369–3376

    CAS  Google Scholar 

  • Liu H, Xue W, Ge G, Luo X, Li Y, Xiang H et al (2010) Hypoxic preconditioning advances CXCR4 and CXCR7 expression by activating HIF-1α in MSCs. Biochem Biophys Res Commun 401:509–515

    CAS  Google Scholar 

  • Liu GS, Peshavariya HM, Higuchi M, Chan EC, Dusting GJ, Jiang F (2016) Pharmacological priming of adipose-derived stem cells for paracrine VEGF production with deferoxamine. J Tissue Eng Regen Med 10:E167–E176

    CAS  Google Scholar 

  • Liu L, Chen J-X, Zhang X-W, Sun Q, Yang L, Liu A et al (2018) Chemokine receptor 7 overexpression promotes mesenchymal stem cell migration and proliferation via secreting Chemokine ligand 12. Sci Rep 8:204

    PubMed Central  Google Scholar 

  • Locke M, Windsor J, Dunbar PR (2009) Human adipose-derived stem cells: isolation, characterization and applications in surgery. ANZ J Surg 79:235–244

    Google Scholar 

  • Masoud Y, Ramin S, Mahboobeh R, Mehrnoosh M, Fahimeh J, Parastoo K (2019) Effect of lithium and valproate on proliferation and migration of limbal epithelial stem/progenitor cells. Curr Eye Res 44:154–161

    CAS  Google Scholar 

  • Mirahmadi M, Rezanejadbardaji H, Irfan-Maqsood M, Mokhtari MJ, Naderi-Meshkin H (2016a) Stem cell therapy for neurodegenerative diseases: strategies for regeneration against degeneration. Cell Ther Regen Med J 1:3

    Google Scholar 

  • Mirahmadi M, Ahmadiankia N, Naderi-Meshkin H, Heirani-Tabasi A, Bidkhori HR, Afsharian P, Bahrami AR (2016b) Hypoxia and laser enhance expression of SDF-1 in muscles cells. Cell Mol Biol 62:31–37

    CAS  Google Scholar 

  • Mishan MA, Heirani-Tabasi A, Mokhberian N, Hassanzade M, Moghaddam HK, Bahrami AR, Ahmadiankia N (2015) Analysis of chemokine receptor gene expression in esophageal cancer cells compared with breast cancer with insights into metastasis. Iran J Public Health 44:1353–1358

    PubMed Central  Google Scholar 

  • Mishan MA, Ahmadiankia N, Bahrami AR (2016) CXCR4 and CCR7: Two eligible targets in targeted cancer therapy. Cell Biol Int 40:955–967

    CAS  Google Scholar 

  • Naderi-Meshkin H, Bahrami AR, Bidkhori HR, Mirahmadi M, Ahmadiankia N (2015) Strategies to improve homing of mesenchymal stem cells for greater efficacy in stem cell therapy. Cell Biol Int 39:23–34

    CAS  Google Scholar 

  • Naderi-Meshkin H, Matin MM, Heirani‐Tabasi A, Mirahmadi M, Irfan‐Maqsood M, Edalatmanesh MA et al (2016) Injectable hydrogel delivery plus preconditioning of mesenchymal stem cells: exploitation of SDF‐1/CXCR4 axis toward enhancing the efficacy of stem cells’ homing. Cell Biol Int 40:730–741

    CAS  Google Scholar 

  • Onda K, Yoshida H, Hayakari R, Xing F, Wang L, Matsumiya T et al (2016) Desferrioxamine, an iron chelator, induces CXCL8 expression in U373MG human astrocytoma cells. Hirosaki Med J 66:127–134

    CAS  Google Scholar 

  • Oses C, Olivares B, Ezquer M, Acosta C, Bosch P, Donoso M et al (2017) Preconditioning of adipose tissue-derived mesenchymal stem cells with deferoxamine increases the production of pro-angiogenic, neuroprotective and anti-inflammatory factors: potential application in the treatment of diabetic neuropathy. PLoS One 12:e0178011

    PubMed Central  Google Scholar 

  • Peyvandi A, Abbaszadeh HA, Roozbahany NA, Pourbakht A, Khoshsirat S, Niri HH, Peyvandi H, Niknazar S (2018) Deferoxamine promotes mesenchymal stem cell homing in noise-induced injured cochlea through PI 3K/AKT pathway. Cell Prolif 51:e12434

    CAS  PubMed Central  Google Scholar 

  • Sharma M, Afrin F, Tripathi R, Gangenahalli G (2013) Regulated expression of CXCR4 constitutive active mutants revealed the up-modulated chemotaxis and up-regulation of genes crucial for CXCR4 mediated homing and engraftment of hematopoietic stem/progenitor cells. J Stem Cells Regen Med 9:19–27

    CAS  PubMed Central  Google Scholar 

  • Sinn D-I, Kim S-J, Chu K, Jung K-H, Lee S-T, Song E-C et al (2007) Valproic acid-mediated neuroprotection in intracerebral hemorrhage via histone deacetylase inhibition and transcriptional activation. Neurobiol Dis 26:464–472

    CAS  Google Scholar 

  • Smith AN, Willis E, Chan VT, Muffley LA, Isik FF, Gibran NS, Hocking AM (2010) Mesenchymal stem cells induce dermal fibroblast responses to injury. Exp Cell Res 316:48–54

    CAS  Google Scholar 

  • Spaeth E, Klopp A, Dembinski J, Andreeff M, Marini F (2008) Inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells. Gene Ther 15:730–738

    CAS  Google Scholar 

  • Tang H, Sun Y, Shi Z, Huang H, Fang Z, Chen J et al (2013) YKL-40 induces IL-8 expression from bronchial epithelium via MAPK (JNK and ERK) and NF-κB pathways, causing bronchial smooth muscle proliferation and migration. J Immunol 190:438–446

    CAS  PubMed Central  Google Scholar 

  • Timoshenko A, Rastogi S, Lala P (2007) Migration-promoting role of VEGF-C and VEGF-C binding receptors in human breast cancer cells. Br J Cancer 97:1090–1098

    CAS  PubMed Central  Google Scholar 

  • Toosi S, Naderi-Meshkin H, Kalalinia F, Pievandi MT, Hosseinkhani H, Bahrami AR et al (2017) Long bone mesenchymal stem cells (Lb-MSCs): clinically reliable cells for osteo-diseases. Cell Tissue Bank 18:489–500

    CAS  Google Scholar 

  • Tsai L-K, Leng Y, Wang Z, Leeds P, Chuang D-M (2010) The mood stabilizers valproic acid and lithium enhance mesenchymal stem cell migration via distinct mechanisms. Neuropsychopharmacology 35:2225–2237

    CAS  PubMed Central  Google Scholar 

  • Vindis C, Cerretti DP, Daniel TO, Huynh-Do U (2003) EphB1 recruits c-Src and p52Shc to activate MAPK/ERK and promote chemotaxis. J Cell Biol 162:661–671

    CAS  PubMed Central  Google Scholar 

  • Wahl EA, Schenck TL, Machens H-G, Balmayor ER (2016) VEGF released by deferoxamine preconditioned mesenchymal stem cells seeded on collagen-GAG substrates enhances neovascularization. Sci Rep 6:36879

    CAS  PubMed Central  Google Scholar 

  • Wang J, Tsirka SE (2005) Neuroprotection by inhibition of matrix metalloproteinases in a mouse model of intracerebral haemorrhage. Brain 128:1622–1633

    Google Scholar 

  • Wang J, Wang Y, Wang S, Cai J, Shi J, Sui X et al (2015) Bone marrow-derived mesenchymal stem cell-secreted IL-8 promotes the angiogenesis and growth of colorectal cancer. Oncotarget 6:42825–42837

    PubMed Central  Google Scholar 

  • Waugh DJ, Wilson C (2008) The interleukin-8 pathway in cancer. Clin Cancer Res 14:6735–6741

    CAS  Google Scholar 

  • Woo KJ, Lee T-J, Park J-W, Kwon TK (2006) Desferrioxamine, an iron chelator, enhances HIF-1α accumulation via cyclooxygenase-2 signaling pathway. Biochem Biophys Res Commun 343:8–14

    CAS  Google Scholar 

  • Yagi H, Soto-Gutierrez A, Parekkadan B, Kitagawa Y, Tompkins RG, Kobayashi N, Yarmush ML (2010) Mesenchymal stem cells: mechanisms of immunomodulation and homing. Cell Transpl 19:667–679

    PubMed Central  Google Scholar 

  • Yamanegi K, Yamane J, Kobayashi K, Kato-Kogoe N, Ohyama H, Nakasho K et al (2012) Valproic acid cooperates with hydralazine to augment the susceptibility of human osteosarcoma cells to Fas-and NK cell-mediated cell death. Int J Oncol 41:83–91

    CAS  Google Scholar 

  • Yoo HI, Moon YH, Kim MS (2016) Effects of CoCl2 on multi-lineage differentiation of C3H/10T1/2 mesenchymal stem cells. Korean J Physiol Pharmacol 20:53–62

    Google Scholar 

  • Zgouras D, Becker U, Loitsch S, Stein J (2004) Modulation of angiogenesis-related protein synthesis by valproic acid. Biochem Biophys Res Commun 316:693–697

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Stem Cells and Regenerative Medicine Research Group, Academic Center for Education, Culture and Research (ACECR), Khorasan Razavi Branch, Mashhad, Iran

    Asieh Heirani-Tabasi, Mahdi Mirahmadi, Hojjat Naderi-Meshkin, Shirin Toosi, Maryam M. Matin, Hamid Reza Bidkhori & Ahmad Reza Bahrami

  2. Ocular Tissue Engineering Research Center, Research Institute for Ophthalmology and Vision Science, Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Mohammad Amir Mishan

  3. Cell and Molecular Biotechnology Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran

    Maryam M. Matin & Ahmad Reza Bahrami

  4. Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran

    Maryam M. Matin & Ahmad Reza Bahrami

Authors
  1. Asieh Heirani-Tabasi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mahdi Mirahmadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mohammad Amir Mishan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hojjat Naderi-Meshkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shirin Toosi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maryam M. Matin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hamid Reza Bidkhori
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ahmad Reza Bahrami
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ahmad Reza Bahrami.

Ethics declarations

Conflict of interest

All the authors declare that they have no competing interests.

Ethical approval

The institutional review board of Iranian Academic Center for Education, Culture and Research (ACECR) approved the study protocol (IRB No. IR.ACECR.JDM.REC.1396.7). Informed consent was confirmed by the IRB. There are no animal experiments carried out for this article.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Heirani-Tabasi, A., Mirahmadi, M., Mishan, M.A. et al. Comparison the effects of hypoxia-mimicking agents on migration-related signaling pathways in mesenchymal stem cells. Cell Tissue Bank 21, 643–653 (2020). https://doi.org/10.1007/s10561-020-09851-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10561-020-09851-2

Keywords

Search

Navigation