Skip to main content

Advertisement

SpringerLink
Log in

Synergistic vasculogenic effects of AMD3100 and stromal-cell-derived factor-1α in vasa nervorum of the sciatic nerve of mice with diabetic peripheral neuropathy

  • Regular Article
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Autologous endothelial progenitor cell (EPC) transplantation has been suggested as a potential therapeutic approach in diabetic neuropathy (DN). However, such treatment might be limited by safety concerns regarding possible unwanted proliferation or differentiation of the transplanted stem cells. An alternative approach is the stimulation of endogenous bone-marrow-derived EPC (BM-EPC) recruitment into ischemic lesions by the administration of stem cell mobilization agents or chemokines. We first tested the EPC mobilization effect of vascular endothelial growth factor (VEGF) and AMD3100 in a mouse model of diabetes and found that AMD3100 was effective as an EPC mobilization agent, whereas VEGF did not increase circulating EPCs in these animals. Because recent studies have suggested that deceased local expression of stromal-cell-derived factor (SDF)-1α in diabetes is the main cause of defective EPC migration, AMD3100 was administrated systemically to stimulate EPC mobilization and SDF-1α was injected locally to enhance its migration into the streptozotocin-induced DN mice model. This combined therapy increased local expression levels of vasculogenesis-associated factors and newly formed endothelial cells in the sciatic nerve, resulting in the restoration of the sciatic vasa nervorum. The treatment also improved the impaired conduction velocity of the sciatic nerve in DN mice. Thus, AMD3100 might be an effective EPC mobilization agent in diabetes, with local SDF-1α injection synergistically increasing vascularity in diabetic nerves. This represents a novel potential therapeutic option for DN patients.

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
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Aicher A, Heeschen C, Mildner-Rihm C, Urbich C, Ihling C, Technau-Ihling K, Zeiher AM, Dimmeler S (2003) Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat Med 9:1370–1376

    Article  PubMed  CAS  Google Scholar 

  • Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967

    Article  PubMed  CAS  Google Scholar 

  • Byrd N, Grabel L (2004) Hedgehog signaling in murine vasculogenesis and angiogenesis. Trends Cardiovasc Med 14:308–313

    Article  PubMed  CAS  Google Scholar 

  • Calcutt NA, Allendoerfer KL, Mizisin AP, Middlemas A, Freshwater JD, Burgers M, Ranciato R, Delcroix JD, Taylor FR, Shapiro R, Strauch K, Dudek H, Engber TM, Galdes A, Rubin LL, Tomlinson DR (2003) Therapeutic efficacy of sonic hedgehog protein in experimental diabetic neuropathy. J Clin Invest 111:507–514

    PubMed  CAS  Google Scholar 

  • Cameron NE, Cotter MA, Low PA (1991) Nerve blood flow in early experimental diabetes in rats: relation to conduction deficits. Am J Physiol 261:E1–E8

    PubMed  CAS  Google Scholar 

  • Capoccia BJ, Shepherd RM, Link DC (2006) G-CSF and AMD3100 mobilize monocytes into the blood that stimulate angiogenesis in vivo through a paracrine mechanism. Blood 108:2438–2445

    Article  PubMed  CAS  Google Scholar 

  • Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC (2004) Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10:858–864

    Article  PubMed  CAS  Google Scholar 

  • Duda DG, Fukumura D, Jain RK (2004) Role of eNOS in neovascularization: NO for endothelial progenitor cells. Trends Mol Med 10:143–145

    Article  PubMed  CAS  Google Scholar 

  • Fadini GP, Sartore S, Agostini C, Avogaro A (2007) Significance of endothelial progenitor cells in subjects with diabetes. Diabetes Care 30:1305–1313

    Article  PubMed  CAS  Google Scholar 

  • Fernyhough P, Diemel LT, Hardy J, Brewster WJ, Mohiuddin L, Tomlinson DR (1995) Human recombinant nerve growth factor replaces deficient neurotrophic support in the diabetic rat. Eur J Neurosci 7:1107–1110

    Article  PubMed  CAS  Google Scholar 

  • Fernyhough P, Diemel LT, Tomlinson DR (1998) Target tissue production and axonal transport of neurotrophin-3 are reduced in streptozotocin-diabetic rats. Diabetologia 41:300–306

    Article  PubMed  CAS  Google Scholar 

  • Gallagher KA, Liu ZJ, Xiao M, Chen H, Goldstein LJ, Buerk DG, Nedeau A, Thom SR, Velazquez OC (2007) Diabetic impairments in NO-mediated endothelial progenitor cell mobilization and homing are reversed by hyperoxia and SDF-1 alpha. J Clin Invest 117:1249–1259

    Article  PubMed  CAS  Google Scholar 

  • Goldstein LJ, Gallagher KA, Bauer SM, Bauer RJ, Baireddy V, Liu ZJ, Buerk DG, Thom SR, Velazquez OC (2006) Endothelial progenitor cell release into circulation is triggered by hyperoxia-induced increases in bone marrow nitric oxide. Stem Cells 24:2309–2318

    Article  PubMed  CAS  Google Scholar 

  • Hasegawa T, Kosaki A, Shimizu K, Matsubara H, Mori Y, Masaki H, Toyoda N, Inoue-Shibata M, Nishikawa M, Iwasaka T (2006) Amelioration of diabetic peripheral neuropathy by implantation of hematopoietic mononuclear cells in streptozotocin-induced diabetic rats. Exp Neurol 199:274–280

    Article  PubMed  CAS  Google Scholar 

  • Jarajapu YP, Grant MB (2010) The promise of cell-based therapies for diabetic complications: challenges and solutions. Circ Res 106:854–869

    Article  PubMed  CAS  Google Scholar 

  • Jeong JO, Kim MO, Kim H, Lee MY, Kim SW, Ii M, Lee JU, Lee J, Choi YJ, Cho HJ, Lee N, Silver M, Wecker A, Kim DW, Yoon YS (2009) Dual angiogenic and neurotrophic effects of bone marrow-derived endothelial progenitor cells on diabetic neuropathy. Circulation 119:699–708

    Article  PubMed  CAS  Google Scholar 

  • Jiao C, Fricker S, Schatteman GC (2006) The chemokine (C-X-C motif) receptor 4 inhibitor AMD3100 accelerates blood flow restoration in diabetic mice. Diabetologia 49:2786–2789

    Article  PubMed  CAS  Google Scholar 

  • Kalka C, Masuda H, Takahashi T, Kalka-Moll WM, Silver M, Kearney M, Li T, Isner JM, Asahara T (2000) Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci USA 97:3422–3427

    Article  PubMed  CAS  Google Scholar 

  • Kawamoto A, Tkebuchava T, Yamaguchi J, Nishimura H, Yoon YS, Milliken C, Uchida S, Masuo O, Iwaguro H, Ma H, Hanley A, Silver M, Kearney M, Losordo DW, Isner JM, Asahara T (2003) Intramyocardial transplantation of autologous endothelial progenitor cells for therapeutic neovascularization of myocardial ischemia. Circulation 107:461–468

    Article  PubMed  Google Scholar 

  • Kazemi S, Wenzel D, Kolossov E, Lenka N, Raible A, Sasse P, Hescheler J, Addicks K, Fleischmann BK, Bloch W (2002) Differential role of bFGF and VEGF for vasculogenesis. Cell Physiol Biochem 12:55–62

    Article  PubMed  CAS  Google Scholar 

  • Kim H, Park JS, Choi YJ, Kim MO, Huh YH, Kim SW, Han JW, Lee J, Kim S, Houge MA, Ii M, Yoon YS (2009) Bone marrow mononuclear cells have neurovascular tropism and improve diabetic neuropathy. Stem Cells 27:1686–1696

    Article  PubMed  CAS  Google Scholar 

  • Kusano KF, Allendoerfer KL, Munger W, Pola R, Bosch-Marce M, Kirchmair R, Yoon YS, Curry C, Silver M, Kearney M, Asahara T, Losordo DW (2004) Sonic hedgehog induces arteriogenesis in diabetic vasa nervorum and restores function in diabetic neuropathy. Arterioscler Thromb Vasc Biol 24:2102–2107

    Article  PubMed  CAS  Google Scholar 

  • Leng Q, Nie Y, Zou Y, Chen J (2008) Elevated CXCL12 expression in the bone marrow of NOD mice is associated with altered T cell and stem cell trafficking and diabetes development. BMC Immunol 9:51

    Article  PubMed  Google Scholar 

  • Loomans CJ, de Koning EJ, Staal FJ, Rookmaaker MB, Verseyden C, de Boer HC, Verhaar MC, Braam B, Rabelink TJ, van Zonneveld AJ (2004) Endothelial progenitor cell dysfunction: a novel concept in the pathogenesis of vascular complications of type 1 diabetes. Diabetes 53:195–199

    Article  PubMed  CAS  Google Scholar 

  • Massberg S, Konrad I, Schürzinger K, Lorenz M, Schneider S, Zohlnhoefer D, Hoppe K, Schiemann M, Kennerknecht E, Sauer S, Schulz C, Kerstan S, Rudelius M, Seidl S, Sorge F, Langer H, Peluso M, Goyal P, Vestweber D, Emambokus NR, Busch DH, Frampton J, Gawaz M (2006) Platelets secrete stromal cell-derived factor 1alpha and recruit bone marrow-derived progenitor cells to arterial thrombi in vivo. J Exp Med 203:1221–1233

    Article  PubMed  CAS  Google Scholar 

  • Mochizuki Y, Ojima K, Uezumi A, Masuda S, Yoshimura K, Takeda S (2005) Participation of bone marrow-derived cells in fibrotic changes in denervated skeletal muscle. Am J Pathol 166:1721–1732

    Article  PubMed  CAS  Google Scholar 

  • Nakae M, Kamiya H, Naruse K, Horio N, Ito Y, Mizubayashi R, Hamada Y, Nakashima E, Akiyama N, Kobayashi Y, Watarai A, Kimura N, Horiguchi M, Tabata Y, Oiso Y, Nakamura J (2006) Effects of basic fibroblast growth factor on experimental diabetic neuropathy in rats. Diabetes 55:1470–1477

    Article  PubMed  CAS  Google Scholar 

  • Naruse K, Hamada Y, Nakashima E, Kato K, Mizubayashi R, Kamiya H, Yuzawa Y, Matsuo S, Murohara T, Matsubara T, Oiso Y, Nakamura J (2005) Therapeutic neovascularization using cord blood-derived endothelial progenitor cells for diabetic neuropathy. Diabetes 54:1823–1828

    Article  PubMed  CAS  Google Scholar 

  • Nishimura Y, Ii M, Qin G, Hamada H, Asai J, Takenaka H, Sekiguchi H, Renault MA, Jujo K, Katoh N, Kishimoto S, Ito A, Kamide C, Kenny J, Millay M, Misener S, Thorne T, Losordo DW (2012) CXCR4 antagonist AMD3100 accelerates impaired wound healing in diabetic mice. J Invest Dermatol 132:711–720

    Article  PubMed  CAS  Google Scholar 

  • Park L, Raman KG, Lee KJ, Lu Y, Ferran LJ Jr, Chow WS, Stern D, Schmidt AM (1998) Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts. Nat Med 4:1025–1031

    Article  PubMed  CAS  Google Scholar 

  • Petit I, Jin D, Rafii S (2007) The SDF-1-CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis. Trends Imunol 28:299–307

    Article  CAS  Google Scholar 

  • Pitchford SC, Furze RC, Jones CP, Wengner AM, Rankin SM (2009) Differential mobilization of subsets of progenitor cells from the bone marrow. Cell Stem Cell 4:62–72

    Article  PubMed  CAS  Google Scholar 

  • Romagnani P, Annunziato F, Liotta F, Lazzeri E, Mazzinghi B, Frosali F, Cosmi L, Maggi L, Lasagni L, Scheffold A, Kruger M, Dimmeler S, Marra F, Gensini G, Maggi E, Romagnani S (2005) CD14+CD34low cells with stem cell phenotypic and functional features are the major source of circulating endothelial progenitors. Circ Res 97:314–322

    Article  PubMed  CAS  Google Scholar 

  • Schratzberger P, Walter DH, Rittig K, Bahlmann FH, Pola R, Curry C, Silver M, Krainin JG, Weinberg DH, Ropper AH, Isner JM (2001) Reversal of experimental diabetic neuropathy by VEGF gene transfer. J Clin Invest 107:1083–1092

    Article  PubMed  CAS  Google Scholar 

  • Shepherd RM, Capoccia BJ, Devine SM, Dipersio J, Trinkaus KM, Ingram D, Link DC (2006) Angiogenic cells can be rapidly mobilized and efficiently harvested from the blood following treatment with AMD3100. Blood 108:3662–3667

    Article  PubMed  CAS  Google Scholar 

  • Shibata T, Naruse K, Kamiya H, Kozakae M, Kondo M, Yasuda Y, Nakamura N, Ota K, Tosaki T, Matsuki T, Nakashima E, Hamada Y, Oiso Y, Nakamura J (2008) Transplantation of bone marrow-derived mesenchymal stem cells improves diabetic polyneuropathy in rats. Diabetes 57:3099–3107

    Article  PubMed  CAS  Google Scholar 

  • Shyu WC, Lin SZ, Chiang MF, Su CY, Li H (2006) Intracerebral peripheral blood stem cell (CD34+) implantation induces neuroplasticity by enhancing beta1 integrin-mediated angiogenesis in chronic stroke rats. J Neurosci 26:3444–3453

    Article  PubMed  CAS  Google Scholar 

  • Tepper OM, Galiano RD, Capla JM, Kalka C, Gagne PJ, Jacobowitz GR, Levine JP, Gurtner GC (2002) Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation 106:2781–2786

    Article  PubMed  Google Scholar 

  • Tepper OM, Capla JM, Galiano RD, Ceradini DJ, Callaghan MJ, Kleinman ME, Gurtner GC (2005) Adult vasculogenesis occurs through in situ recruitment, proliferation, and tubulization of circulating bone marrow-derived cells. Blood 105:1068–1077

    Article  PubMed  CAS  Google Scholar 

  • Thum T, Fraccarollo D, Schultheiss M, Froese S, Galuppo P, Widder JD, Tsikas D, Ertl G, Bauersachs J (2007) Endothelial nitric oxide synthase uncoupling impairs endothelial progenitor cell mobilization and function in diabetes. Diabetes 56:666–674

    Article  PubMed  CAS  Google Scholar 

  • Yamaguchi J, Kusano KF, Masuo O, Kawamoto A, Silver M, Murasawa S, Bosch-Marce M, Masuda H, Losordo DW, Isner JM, Asahara T (2003) Stromal cell-derived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization. Circulation 107:1322–1328

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Stem Cell Neuroplasticity Research Group, Kyungpook National University, Daegu, South Korea

    Bae Jin Kim, Jong Kil Lee, Hee Kyung Jin & Jae-sung Bae

  2. Department of Physiology, Cell and Matrix Research Institute, World Class University Program, School of Medicine, Kyungpook National University, 101 Dongindong 2Ga, Jung-Gu, Daegu, 700-422, South Korea

    Bae Jin Kim, Jong Kil Lee & Jae-sung Bae

  3. Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA

    Edward H. Schuchman

  4. Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, 1370 Sankyuk-dong, Buk-gu, Daegu, 702-701, South Korea

    Hee Kyung Jin

Authors
  1. Bae Jin Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jong Kil Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Edward H. Schuchman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hee Kyung Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jae-sung Bae
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Hee Kyung Jin or Jae-sung Bae.

Additional information

B.J.K. and J.K.L. contributed equally to this work.

This work was supported by a grant of the Bio & Medical Technology Development Program (2012M3A9C6049913, 2010-0020234) and World Class University Program (R32-10064) of the National Research Foundation (NRF) of Korea funded by the Ministry of Education, Science and Technology, Republic of Korea. It was also supported by the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A084065).

The authors declare no potential conflicts of interest.

J.S.B. designed all experiments; B.J.K., J.K.L. and H.K.J. performed the experiments; H.K.J. and J.S.B. supervised the project; B.J.K. and J.K.L. wrote the manuscript; J.S.B. and E.H.S. edited and reviewed the manuscript.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Fig. 1

Co-treatment of AMD3100 and SDF-1α induces the restoration of sciatic vasa nervorum but the effects last less than 3 weeks. Sciatic nerve vasa nervorum were stained by in vivo perfusion with FITC-conjugated BS-1 lectin at 21 days after treatment. a Representative fluorescence images of cross-sections of BS-1-lectin-perfused mouse sciatic nerves. Bar 50 μm. b The number of vessels per cross-section was quantified. The number of vessels was not significantly different between all experimental groups (n = 3 per group). Data represent means ± SEM. Tukey’s HSD test. (JPEG 48 kb)

High-resolution Image

(TIFF 430 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, B.J., Lee, J.K., Schuchman, E.H. et al. Synergistic vasculogenic effects of AMD3100 and stromal-cell-derived factor-1α in vasa nervorum of the sciatic nerve of mice with diabetic peripheral neuropathy. Cell Tissue Res 354, 395–407 (2013). https://doi.org/10.1007/s00441-013-1689-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-013-1689-4

Keywords

Search

Navigation