Diabetes Limits Stem Cell Mobilization Following G-CSF but Not Plerixafor

Gian Paolo Fadini, Mark Fiala, Roberta Cappellari, Marianna Danna, Soo Park, Nicol Poncina, Lisa Menegazzo, Mattia Albiero, John DiPersio, Keith Stockerl-Goldstein, Angelo Avogaro, Gian Paolo Fadini, Mark Fiala, Roberta Cappellari, Marianna Danna, Soo Park, Nicol Poncina, Lisa Menegazzo, Mattia Albiero, John DiPersio, Keith Stockerl-Goldstein, Angelo Avogaro

Abstract

Previous studies suggest that diabetes impairs hematopoietic stem cell (HSC) mobilization in response to granulocyte colony-stimulating factor (G-CSF). In this study, we tested whether the CXCR4 antagonist plerixafor, differently from G-CSF, is effective in mobilizing HSCs in patients with diabetes. In a prospective study, individuals with and without diabetes (n = 10/group) were administered plerixafor to compare CD34(+) HSC mobilization; plerixafor was equally able to mobilize CD34(+) HSCs in the two groups, whereas in historical data, G-CSF was less effective in patients with diabetes. In a retrospective autologous transplantation study conducted on 706 patients, diabetes was associated with poorer mobilization in patients who received G-CSF with/without chemotherapy, whereas it was not in patients who received G-CSF plus plerixafor. Similarly in an allogeneic transplantation study (n = 335), diabetes was associated with poorer mobilization in patients who received G-CSF. Patients with diabetes who received G-CSF without plerixafor had a lower probability of reaching >50/μL CD34(+) HSCs, independent from confounding variables. In conclusion, diabetes negatively impacted HSC mobilization after G-CSF with or without chemotherapy but had no effect on mobilization induced by G-CSF with plerixafor. This finding has major implications for the care of patients with diabetes undergoing stem cell mobilization and transplantation and for the vascular regenerative potential of bone marrow stem cells.

Trial registration: ClinicalTrials.gov NCT02056210.

© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Figures

Figure 1
Figure 1
Summary results of the prospective plerixafor trial and comparison with historical G-CSF data. For subjects with and without diabetes, changes in the levels of CD34+ HSCs, as well as HSC colonies after plerixafor are reported as box and whisker plot, individual patient lines, and fold changes. *P < 0.05 vs. baseline or vs. nondiabetic (for fold-change comparison). CFU-GM, colony-forming units–granulocyte macrophage.
Figure 2
Figure 2
Achieved CD34+ HSC count in the retrospective studies. Patients undergoing HSC mobilization and collection for autologous transplantation (auto) were divided into those who received G-CSF with or without chemotherapy and those who received G-CSF with plerixafor. Subjects undergoing HSC mobilization and collection for allogeneic donation (allo) only received G-CSF. Then patients were divided based on a history of diabetes (DM) or not (CTRL). *P < 0.05 DM vs. CTRL.

References

    1. Seshasai SR, Kaptoge S, Thompson A, et al. .; Emerging Risk Factors Collaboration . Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med 2011;364:829–841
    1. Oikawa A, Siragusa M, Quaini F, et al. . Diabetes mellitus induces bone marrow microangiopathy. Arterioscler Thromb Vasc Biol 2010;30:498–508
    1. Albiero M, Poncina N, Tjwa M, et al. . Diabetes causes bone marrow autonomic neuropathy and impairs stem cell mobilization via dysregulated p66Shc and Sirt1. Diabetes 2014;63:1353–1365
    1. Spinetti G, Cordella D, Fortunato O, et al. . Global remodeling of the vascular stem cell niche in bone marrow of diabetic patients: implication of the microRNA-155/FOXO3a signaling pathway. Circ Res 2013;112:510–522
    1. Ferraro F, Lymperi S, Mendez-Ferrer S, et al. Diabetes impairs hematopoietic stem cell mobilization by altering niche function. Sci Transl Med 2011;3:104ra101
    1. Fadini GP, Albiero M, Vigili de Kreutzenberg S, et al. . Diabetes impairs stem cell and proangiogenic cell mobilization in humans. Diabetes Care 2013;36:943–949
    1. Fadini GP, Avogaro A. Diabetes impairs mobilization of stem cells for the treatment of cardiovascular disease: a meta-regression analysis. Int J Cardiol 2013;168:892–897
    1. DiPersio JF. Diabetic stem-cell “mobilopathy”. N Engl J Med 2011;365:2536–2538
    1. Fadini GP, Losordo D, Dimmeler S. Critical reevaluation of endothelial progenitor cell phenotypes for therapeutic and diagnostic use. Circ Res 2012;110:624–637
    1. Fadini GP, Ferraro F, Quaini F, Asahara T, Madeddu P. Concise review: diabetes, the bone marrow niche, and impaired vascular regeneration. Stem Cells Transl Med 2014;3:949–957
    1. Moazzami K, Roohi A, Moazzami B. Granulocyte colony stimulating factor therapy for acute myocardial infarction. Cochrane Database Syst Rev 2013;5:CD008844.
    1. Fadini GP. A reappraisal of the role of circulating (progenitor) cells in the pathobiology of diabetic complications. Diabetologia 2014;57:4–15
    1. Albiero M, Avogaro A, Fadini GP. Restoring stem cell mobilization to promote vascular repair in diabetes. Vascul Pharmacol 2013;58:253–258
    1. Winkler IG, Pettit AR, Raggatt LJ, et al. . Hematopoietic stem cell mobilizing agents G-CSF, cyclophosphamide or AMD3100 have distinct mechanisms of action on bone marrow HSC niches and bone formation. Leukemia 2012;26:1594–1601
    1. Petit I, Szyper-Kravitz M, Nagler A, et al. . G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat Immunol 2002;3:687–694
    1. Broxmeyer HE, Orschell CM, Clapp DW, et al. . Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. J Exp Med 2005;201:1307–1318
    1. Nademanee AP, DiPersio JF, Maziarz RT, et al. . Plerixafor plus granulocyte colony-stimulating factor versus placebo plus granulocyte colony-stimulating factor for mobilization of CD34(+) hematopoietic stem cells in patients with multiple myeloma and low peripheral blood CD34(+) cell count: results of a subset analysis of a randomized trial. Biol Blood Marrow Transplant 2012;18:1564–1572
    1. Capoccia BJ, Shepherd RM, Link DC. G-CSF and AMD3100 mobilize monocytes into the blood that stimulate angiogenesis in vivo through a paracrine mechanism. Blood 2006;108:2438–2445
    1. Nishimura Y, Ii M, Qin G, et al. . CXCR4 antagonist AMD3100 accelerates impaired wound healing in diabetic mice. J Invest Dermatol 2012;132:711–720
    1. Tepper OM, Carr J, Allen RJ Jr, et al. . Decreased circulating progenitor cell number and failed mechanisms of stromal cell-derived factor-1alpha mediated bone marrow mobilization impair diabetic tissue repair. Diabetes 2010;59:1974–1983
    1. Hibbert B, Simard T, Ramirez FD, et al. . The effect of statins on circulating endothelial progenitor cells in humans: a systematic review. J Cardiovasc Pharmacol 2013;62:491–496
    1. Olivieri A, Offidani M, Montanari M, et al. . Factors affecting hemopoietic recovery after high-dose therapy and autologous peripheral blood progenitor cell transplantation: a single center experience. Haematologica 1998;83:329–337
    1. Watts MJ, Sullivan AM, Jamieson E, et al. . Progenitor-cell mobilization after low-dose cyclophosphamide and granulocyte colony-stimulating factor: an analysis of progenitor-cell quantity and quality and factors predicting for these parameters in 101 pretreated patients with malignant lymphoma. J Clin Oncol 1997;15:535–546
    1. Katayama Y, Battista M, Kao WM, et al. . Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 2006;124:407–421
    1. Christopherson KW 2nd, Cooper S, Broxmeyer HE. Cell surface peptidase CD26/DPPIV mediates G-CSF mobilization of mouse progenitor cells. Blood 2003;101:4680–4686
    1. Broxmeyer HE, Hoggatt J, O’Leary HA, et al. . Dipeptidylpeptidase 4 negatively regulates colony-stimulating factor activity and stress hematopoiesis. Nat Med 2012;18:1786–1796
    1. Chow A, Lucas D, Hidalgo A, et al. . Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. J Exp Med 2011;208:261–271
    1. Fadini GP, Albiero M, Seeger F, et al. . Stem cell compartmentalization in diabetes and high cardiovascular risk reveals the role of DPP-4 in diabetic stem cell mobilopathy. Basic Res Cardiol 2013;108:313.
    1. Fadini GP, Sartore S, Schiavon M, et al. . Diabetes impairs progenitor cell mobilisation after hindlimb ischaemia-reperfusion injury in rats. Diabetologia 2006;49:3075–3084
    1. Ling L, Shen Y, Wang K, et al. . Worse clinical outcomes in acute myocardial infarction patients with type 2 diabetes mellitus: relevance to impaired endothelial progenitor cells mobilization. PLoS ONE 2012;7:e50739.
    1. Urbich C, Dimmeler S. Endothelial progenitor cells: characterization and role in vascular biology. Circ Res 2004;95:343–353
    1. Couri CE, Oliveira MC, Stracieri AB, et al. . C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA 2009;301:1573–1579
    1. Pusic I, Jiang SY, Landua S, et al. . Impact of mobilization and remobilization strategies on achieving sufficient stem cell yields for autologous transplantation. Biol Blood Marrow Transplant 2008;14:1045–1056

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다