Skip to main content
Log in

Stromal-Derived Factor-1 Alpha-Loaded PLGA Microspheres for Stem Cell Recruitment

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

ABSTRACT

Purpose

Stromal-derived factor-1 alpha (SDF-1α) is a chemoattractant that has been investigated for treating various diseases, with the goal of recruiting endogenous stem cells to the site of injury. Biodegradable PLGA microspheres were investigated as a means to deliver SDF-1α in a sustained-release manner.

Methods

We encapsulated SDF-1α into biodegradable poly(lactide-co-glycolide) (PLGA) microspheres using a double-emulsion solvent extraction/evaporation technique. We varied several formulation parameters, characterized the in vitro release profile of SDF-1α and the size and morphology of microspheres, and determined the bioactivity of the released SDF-1α of stimulating migration of mesenchymal stem cells (MSCs).

Results

We found that microspheres fabricated using end-capped PLGA, BSA as an excipient, and low solvent volumes yielded a high encapsulation efficiency (>64%) and released SDF-1α over a >50-day timeframe. The released SDF-1α was bioactive and caused significant migration of MSCs throughout the duration of release from the microspheres.

Conclusions

We have identified several variables that led to successful encapsulation of SDF-1α into PLGA microspheres. We envision that SDF-lα-loaded microspheres may serve as injectable sources of sustained-release chemokine for promoting the recruitment of endogenous stem cells to the site of injury.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

REFERENCES

  1. Kim S, De Vellis J. Stem cell-based cell therapy in neurological diseases: a review. J Neurosci Res. 2009;87:2183–200.

    Article  PubMed  CAS  Google Scholar 

  2. Lindvall O, Kokaia Z. Stem cells for the treatment of neurological disorders. Nature. 2006;441:1094–6.

    Article  PubMed  CAS  Google Scholar 

  3. Siniscalco D, Sullo N, Maione S, Rossi F, D’Agostino B. Stem cell therapy: the great promise in lung disease. Ther Adv Respir Dis. 2008;2:173–7.

    Article  PubMed  Google Scholar 

  4. Branski LK, Gauglitz GG, Herndon DN, Jeschke MG. A review of gene and stem cell therapy in cutaneous wound healing. Burns. 2009;35:171–80.

    Article  PubMed  Google Scholar 

  5. Segers VF, Lee R. Stem-cell therapy for cardiac disease. Nature. 2008;451:937–42.

    Article  PubMed  CAS  Google Scholar 

  6. Chavakis E, Urbich C, Dimmeler S. Homing and engraftment of progenitor cells: a prerequisite for cell therapy. J Mol Cell Cardiol. 2008;45:514–22.

    Article  PubMed  CAS  Google Scholar 

  7. Teng CJ, Luo J, Chiu RC, Shum-Tim D. Massive mechanical loss of microspheres with direct intramyocardial injection in the beating heart: implications for cellular cardiomyoplasty. J Thorac Cardiovasc Surg. 2006;132:628–32.

    Article  PubMed  Google Scholar 

  8. Laflamme MA, Zbinden S, Epstein SE, Murry CE. Cell-based therapy for myocardial ischemia and infarction: pathophysiological mechanisms. Annu Rev Pathol. 2007;2:307–39.

    Article  PubMed  CAS  Google Scholar 

  9. Ghadge SK, Muhlstedt S, Ozcelik C, Bader M. SDF-1alpha as a therapeutic stem cell homing factor in myocardial infarction. Pharmacol Ther. 2011;129:97–108.

    Article  PubMed  CAS  Google Scholar 

  10. Imitola J, Raddassi K, Park K, Mueller FJ, Nieto M, Teng Y, et al. Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway. Proc Natl Acad Sci U S A. 2004;101:18117–22.

    Article  PubMed  CAS  Google Scholar 

  11. Vandervelde S, Van Luyn MJ, Tio RA, Harmsen MC. Signaling factors in stem cell-mediated repair of infarcted myocardium. J Mol Cell Cardiol. 2005;39:363–76.

    Article  PubMed  CAS  Google Scholar 

  12. Wang F, Yasuhara T, Shingo T, Kameda M, Tajiri N, Yuan WJ, et al. Intravenous administration of mesenchymal stem cells exerts therapeutic effects on parkinsonian model of rats: focusing on neuroprotective effects of stromal cell-derived factor-1alpha. BMC Neurosci. 2010;11:52.

    Article  PubMed  CAS  Google Scholar 

  13. Askari AT, Unzek S, Popovic ZB, Goldman CK, Forudi F, Kiedrowski M, et al. Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. Lancet. 2003;362:697–703.

    Article  PubMed  CAS  Google Scholar 

  14. Wei YJ, Tang Y, Li J, Cui CJ, Zhang H, Zhang XL, et al. Cloning and expression pattern of dog SDF-1 and the implications of altered expression of SDF-1 in ischemic myocardium. Cytokine. 2007;40:52–9.

    Article  PubMed  CAS  Google Scholar 

  15. Zhang G, Nakamura Y, Wang X, Hu Q, Suggs LJ, Zhang J. Controlled release of stromal cell-derived factor-1 alpha in situ increases c-kit + cell homing to the infarcted heart. Tissue Eng. 2007;13:2063–71.

    Article  PubMed  CAS  Google Scholar 

  16. Elmadbouh I, Haider HK, Jiang S, Idris NM, Lu G, Ashraf M. Ex vivo delivered stromal cell-derived factor-1alpha promotes stem cell homing and induces angiomyogenesis in the infarcted myocardium. J Mol Cell Cardiol. 2007;42:792–803.

    Article  PubMed  CAS  Google Scholar 

  17. Zhang M, Mal N, Kiedrowski M, Chacko M, Askari AT, Popovic ZB, et al. SDF-1 expression by mesenchymal stem cells results in trophic support of cardiac myocytes after myocardial infarction. FASEB J. 2007;21:3197–207.

    Article  PubMed  CAS  Google Scholar 

  18. Segers VF, Tokunou T, Higgins LJ, Macgillivray C, Gannon J, Lee RT. Local delivery of protease-resistant stromal cell derived factor-1 for stem cell recruitment after myocardial infarction. Circulation. 2007;116:1683–92.

    Article  PubMed  CAS  Google Scholar 

  19. Zaruba MM, Theiss HD, Vallaster M, Mehl U, Brunner S, David R, et al. Synergy between CD26/DPP-IV inhibition and G-CSF improves cardiac function after acute myocardial infarction. Cell Stem Cell. 2009;4:313–23.

    Article  PubMed  CAS  Google Scholar 

  20. Cleland JL. Protein delivery from biodegradable microspheres. Pharm Biotechnol. 1997;10:1–43.

    Article  PubMed  CAS  Google Scholar 

  21. Shive M, Anderson J. Biodegradation and biocompatibility of PLA and PLGA microspheres. Adv Drug Deliv Rev. 1997;28:5–24.

    Article  PubMed  Google Scholar 

  22. Xu X, Yu H, Gao S, Ma HQ, Leong KW, Wang S. Polyphosphoester microspheres for sustained release of biologically active nerve growth factor. Biomaterials. 2002;23:3765–72.

    Article  PubMed  CAS  Google Scholar 

  23. Nakamura Y, Wang X, Xu C, Asakura A, Yoshiyama M, From A, et al. Xenotransplantation of long-term-cultured swine bone marrow-derived mesenchymal stem cells. Stem Cells. 2007;25:612–20.

    Article  PubMed  CAS  Google Scholar 

  24. Wilber A, Linehan JL, Tian X, Woll PS, Morris JK, Belur LR, et al. Efficient and stable transgene expression in human embryonic stem cells using transposon-mediated gene transfer. Stem Cells. 2007;25:2919–27.

    Article  PubMed  CAS  Google Scholar 

  25. Ponte A, Marais E, Gallay N, Langonne A, Delorme B, Herault O, et al. The in vitro migration capacity of human bone marrow mesenchymal stem cells: comparison of chemokine and growth factor chemotactic activities. Stem Cells. 2007;25:1737–45.

    Article  PubMed  CAS  Google Scholar 

  26. Hamada T, Mohle R, Hesselgesser J, Hoxie J, Nachman RL, Moore MA, et al. Transendothelial migration of megakaryocytes in response to stromal cell-derived factor 1 (SDF-1) enhances platelet formation. J Exp Med. 1998;188:539–48.

    Article  PubMed  CAS  Google Scholar 

  27. Yamaguchi J, Kusano KF, Masuo O, Kawamoto A, Silver M, Murasawa S, et al. Stromal cell-derived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization. Circulation. 2003;107:1322–8.

    Article  PubMed  CAS  Google Scholar 

  28. Kitaori T, Ito H, Schwarz E, Tsutsumi R, Yoshitomi H, Oishi S, et al. Stromal cell-derived factor 1/CXCR4 signaling is critical for the recruitment of mesenchymal stem cells to the fracture site during skeletal repair in a mouse model. Arthritis Rheum. 2009;60:813–23.

    Article  PubMed  CAS  Google Scholar 

  29. Mundargi R, Babu V, Rangaswamy V, Patel P, Aminabhavi T. Nano/micro technologies for delivering macromolecular therapeutics using poly(D, L-lactide-co-glycolide) and its derivatives. J Control Release. 2008;125:193–209.

    Article  PubMed  CAS  Google Scholar 

  30. Bilati U, Allemann E, Doelker E. Strategic approaches for overcoming peptide and protein instability within biodegradable nano- and microparticles. Eur J Pharm Biopharm. 2005;59:375–88.

    Article  PubMed  CAS  Google Scholar 

  31. Jaklenec A, Hinckfuss A, Bilgen B, Ciombor DM, Aaron R, Mathiowitz E. Sequential release of bioactive IGF-I and TGF-beta 1 from PLGA microsphere-based scaffolds. Biomaterials. 2008;29:1518–25.

    Article  PubMed  CAS  Google Scholar 

  32. Yeo Y, Park K. Control of encapsulation efficiency and initial burst in polymeric microparticle systems. Arch Pharm Res. 2004;27:1–12.

    Article  PubMed  CAS  Google Scholar 

  33. Zhu XH, Wang CH, Tong YW. In vitro characterization of hepatocyte growth factor release from PHBV/PLGA microsphere scaffold. J Biomed Mater Res A. 2009;89:411–23.

    PubMed  Google Scholar 

  34. Böhme U, Scheler U. Effective charge of bovine serum albumin determined by electrophoresis NMR. Chemical Physics Letters. 2007;435:342–5.

    Article  Google Scholar 

  35. Luo J, Luo Z, Zhou N, Hall J, Huang Z. Attachment of C-terminus of SDF-1 enhances the biological activity of its N-terminal peptide. Biochem Biophys Res Commun. 1999;264:42–7.

    Article  PubMed  CAS  Google Scholar 

  36. Ando S, Putnam D, Pack DW, Langer R. PLGA microspheres containing plasmid DNA: preservation of supercoiled DNA via cryopreparation and carbohydrate stabilization. J Pharm Sci. 1999;88:126–30.

    Article  PubMed  CAS  Google Scholar 

  37. Crotts G, Park TG. Preparation of porous and nonporous biodegradable polymeric hollow microspheres. Journal of Controlled Release. 1995;35:91–105.

    Article  CAS  Google Scholar 

  38. Chung TW, Tsai YL, Hsieh JH, Tsai WJ. Different ratios of lactide and glycolide in PLGA affect the surface property and protein delivery characteristics of the PLGA microspheres with hydrophobic additives. J Microencapsul. 2006;23:15–27.

    Article  PubMed  CAS  Google Scholar 

  39. Chen XQ, Yang YY, Wang L, Chung TS. Effects of inner water volume on the peculiar surface morphology of microspheres fabricated by double emulsion technique. J Microencapsul. 2001;18:637–49.

    Article  PubMed  CAS  Google Scholar 

  40. Abbott JD, Huang Y, Liu D, Hickey R, Krause DS, Giordano FJ. Stromal cell-derived factor-1alpha plays a critical role in stem cell recruitment to the heart after myocardial infarction but is not sufficient to induce homing in the absence of injury. Circulation. 2004;110:3300–5.

    Article  PubMed  Google Scholar 

  41. Ji J, He B, Dheen S, Tay S. Interactions of chemokines and chemokine receptors mediate the migration of mesenchymal stem cells to the impaired site in the brain after hypoglossal nerve injury. Stem Cells. 2004;22:415–27.

    Article  PubMed  CAS  Google Scholar 

  42. Starr AE, Overall CM. Methods in Enzymology: Chemokines, Part B. San Diego: Academic Press; 2009:298.

  43. Zhao X, Jain S, Larman HB, Gonzalez S, Irvine DJ. Directed cell migration via chemoattractants released from degradable microspheres. Biomaterials. 2005;26:5048–63.

    Article  PubMed  CAS  Google Scholar 

Download references

ACKNOWLEDGMENTS

This work is supported in part by the University of Minnesota’s Institute for Engineering in Medicine (IEM) and an NIH Biotechnology Training Grant (Grant Number T32 GM008347). Special thanks to Dr. Jianyi Zhang (Department of Medicine, University of Minnesota) for kindly providing the GFP-expressing porcine MSCs. We are also grateful to Dr. Nathan Lockwood for his careful review and critique of the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Chun Wang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cross, D.P., Wang, C. Stromal-Derived Factor-1 Alpha-Loaded PLGA Microspheres for Stem Cell Recruitment. Pharm Res 28, 2477–2489 (2011). https://doi.org/10.1007/s11095-011-0474-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-011-0474-x

KEY WORDS

Navigation