Acta Diabetologica

, Volume 55, Issue 5, pp 419–427 | Cite as

Identification of megakaryocytes as a target of advanced glycation end products in diabetic complications in bone marrow

  • Benfang Wang
  • Jianjiang Yu
  • Ting Wang
  • Ying Shen
  • Dandan Lin
  • Xin Xu
  • Yiqiang Wang
Original Article

Abstract

Aims

To define the possible effect of diabetic conditions on megakaryocytes, the long-know precursors of platelets and lately characterized modulator of hematopoietic stem quiescence–activation transition.

Methods

Megakaryoblastic MEG-01 cell culture and TPO/SCF/IL-3-induced differentiation of human umbilical blood mononuclear cells toward megakaryocytes were used to test effects of glycated bovine serum albumin (BSA-AGEs). The ob/ob mice and streptozotocin-treated mice were used as models of hyperglycemia. MTT was used to measure cell proliferation, FACS for surface marker and cell cycle, and RT-qPCR for the expression of interested genes. Megakaryocytes at different stages in marrow smear were checked under microscope.

Results

When added in MEG-01 cultures at 200 μg/ml, BSA-AGEs increased proliferation of cells and enhanced mRNA expression of RAGE, VEGFα and PF4 in the cells. None of cell cycle distribution, PMA-induced platelet-like particles production, expression of GATA1/NF-E2/PU-1/IL-6/OPG/PDGF in MEG-01 cells nor TPO/SCF/IL-3 induced umbilical cord blood cells differentiation into megakaryocyte was affected by BSA-AGEs. In the ob/ob diabetic mice, MKs percentages in marrow cells and platelets in peripheral blood were significantly increased compared with control mice. In streptozotocin-induced diabetic mice, however, MKs percentage in marrow cells was decreased though peripheral platelet counts were not altered. Gene expression assay showed that the change in MKs in these two diabetic conditions might be explained by the alteration of GATA1 and NF-E2 expression, respectively.

Conclusions

Diabetic condition in animals might exert its influence on hematopoiesis via megakaryocytes—the newly identified modulator of hematopoietic stem cells in bone marrow.

Keywords

Advanced glycation end products Diabetes Megakaryocytes Hematopoiesis Bone marrow 

Notes

Acknowledgements

This work was supported by an unrestricted starting package of The First Affiliated Hospital of Soochow University to Yiqiang Wang and a Grant from the National Science Foundation of China (81600076) to Dandan Lin.

Compliance with ethical standards

Conflict of interest

The authors did not declare any potential conflicts of interest.

Ethical approval

All experimental protocols procedures performed in studies involving human participants or animal use were approved by the Review Board of The First Affiliated Hospital of Soochow University (permit number FYY2016-NSFC-81600076) in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards the Chinese Ministry of Science and Technology Guidelines on the Humane Treatment of Laboratory Animals (vGKFCZ-2006-398).

Informed consent

In studies using human umbilical cord blood, informed consent was obtained from all individual participants included.

References

  1. 1.
    Prisco D, Paniccia R, Coppo M et al (1989) Red blood cell lipid alterations in type II diabetes mellitus. Thromb Res 54:751–758CrossRefPubMedGoogle Scholar
  2. 2.
    Tan JS, Anderson JL, Watanakunakorn C, Phair JP (1975) Neutrophil dysfunction in diabetes mellitus. J Lab Clin Med 85:26–33PubMedGoogle Scholar
  3. 3.
    Jones RJ, Delamothe AP, Curtis LD, Machin SJ, Betteridge DJ (1985) Measurement of platelet aggregation in diabetics using the new electronic platelet aggregometer. Diabet Med 2:105–109CrossRefPubMedGoogle Scholar
  4. 4.
    Khullar M, Cheema BS, Raut SK (2017) Emerging evidence of epigenetic modifications in vascular complication of diabetes. Front Endocrinol (Lausanne) 8:237CrossRefGoogle Scholar
  5. 5.
    Tasci I, Basgoz BB, Saglam K (2016) Glycemic control and the risk of microvascular complications in people with diabetes mellitus. Acta Diabetol 53:129–130CrossRefPubMedGoogle Scholar
  6. 6.
    Naqshbandi M, Harris SB, Esler JG, Antwi-Nsiah F (2008) Global complication rates of type 2 diabetes in Indigenous peoples: a comprehensive review. Diabetes Res Clin Pract 82:1–17CrossRefPubMedGoogle Scholar
  7. 7.
    Marzona I, Avanzini F, Lucisano G et al (2017) Are all people with diabetes and cardiovascular risk factors or microvascular complications at very high risk? Findings from the Risk and Prevention Study. Acta Diabetol 54:123–131CrossRefPubMedGoogle Scholar
  8. 8.
    Tadic M, Cuspidi C, Vukomanovic V et al (2016) The influence of type 2 diabetes and arterial hypertension on right ventricular layer-specific mechanics. Acta Diabetol 53:791–797CrossRefPubMedGoogle Scholar
  9. 9.
    Maffi P, Secchi A (2015) Clinical results of islet transplantation. Pharmacol Res 98:86–91CrossRefPubMedGoogle Scholar
  10. 10.
    Bandello F, Lattanzio R, Zucchiatti I, Del Turco C (2013) Pathophysiology and treatment of diabetic retinopathy. Acta Diabetol 50:1–20CrossRefPubMedGoogle Scholar
  11. 11.
    Jerram ST, Dang MN, Leslie RD (2017) The role of epigenetics in type 1 diabetes. Curr Diabetes Rep 17:89CrossRefGoogle Scholar
  12. 12.
    Raciti GA, Longo M, Parrillo L et al (2015) Understanding type 2 diabetes: from genetics to epigenetics. Acta Diabetol 52:821–827CrossRefPubMedGoogle Scholar
  13. 13.
    Barutta F, Bruno G, Matullo G et al (2017) MicroRNA-126 and micro-/macrovascular complications of type 1 diabetes in the EURODIAB Prospective Complications Study. Acta Diabetol 54:133–139CrossRefPubMedGoogle Scholar
  14. 14.
    Songini M, Mannu C, Targhetta C, Bruno G (2017) Type 1 diabetes in Sardinia: facts and hypotheses in the context of worldwide epidemiological data. Acta Diabetol 54:9–17CrossRefPubMedGoogle Scholar
  15. 15.
    Zerbini G, Maestroni S, Turco V, Secchi A (2017) The eye as a window to the microvascular complications of diabetes. Dev Ophthalmol 60:6–15CrossRefPubMedGoogle Scholar
  16. 16.
    Fadini GP (2011) Is bone marrow another target of diabetic complications? Eur J Clin Investig 41:457–463CrossRefGoogle Scholar
  17. 17.
    Fadini GP, Ciciliot S, Albiero M (2017) Concise review: perspectives and clinical implications of bone marrow and circulating stem cell defects in diabetes. Stem Cells 35:106–116CrossRefPubMedGoogle Scholar
  18. 18.
    Fadini GP, Fiala M, Cappellari R et al (2015) Diabetes limits stem cell mobilization following G-CSF but not plerixafor. Diabetes 64:2969–2977CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Yoshida S, Ishikawa F, Kawano N et al (2005) Human cord blood-derived cells generate insulin-producing cells in vivo. Stem Cells 23:1409–1416CrossRefPubMedGoogle Scholar
  20. 20.
    Hussain MA, Theise ND (2004) Stem-cell therapy for diabetes mellitus. Lancet 364:203–205CrossRefPubMedGoogle Scholar
  21. 21.
    Huang P, Li S, Han M, Xiao Z, Yang R, Han ZC (2005) Autologous transplantation of granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells improves critical limb ischemia in diabetes. Diabetes Care 28:2155–2160CrossRefPubMedGoogle Scholar
  22. 22.
    Vrtovec B, Sever M, Jensterle M et al (2016) Efficacy of CD34+ stem cell therapy in nonischemic dilated cardiomyopathy is absent in patients with diabetes but preserved in patients with insulin resistance. Stem Cells Transl Med 5:632–638CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Mangialardi G, Katare R, Oikawa A et al (2013) Diabetes causes bone marrow endothelial barrier dysfunction by activation of the RhoA–Rho-associated kinase signaling pathway. Arterioscler Thromb Vasc Biol 33:555–564CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Spinetti G, Cordella D, Fortunato O et al (2013) Global remodeling of the vascular stem cell niche in bone marrow of diabetic patients: implication of the microRNA-155/FOXO3a signaling pathway. Circ Res 112:510–522CrossRefPubMedGoogle Scholar
  25. 25.
    Ratajczak MZ, Zuba-Surma EK, Machalinski B, Kucia M (2007) Bone-marrow-derived stem cells–our key to longevity? J Appl Genet 48:307–319CrossRefPubMedGoogle Scholar
  26. 26.
    Italiano JE Jr, Shivdasani RA (2003) Megakaryocytes and beyond: the birth of platelets. J Thromb Haemost JTH 1:1174–1182CrossRefPubMedGoogle Scholar
  27. 27.
    Levine RF (1980) Isolation and characterization of normal human megakaryocytes. Br J Haematol 45:487–497CrossRefPubMedGoogle Scholar
  28. 28.
    Yan XQ, Lacey D, Hill D et al (1996) A model of myelofibrosis and osteosclerosis in mice induced by overexpressing thrombopoietin (mpl ligand): reversal of disease by bone marrow transplantation. Blood 88:402–409PubMedGoogle Scholar
  29. 29.
    Dominici M, Rasini V, Bussolari R et al (2009) Restoration and reversible expansion of the osteoblastic hematopoietic stem cell niche after marrow radioablation. Blood 114:2333–2343CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Ciovacco WA, Cheng YH, Horowitz MC, Kacena MA (2010) Immature and mature megakaryocytes enhance osteoblast proliferation and inhibit osteoclast formation. J Cell Biochem 109:774–781PubMedPubMedCentralGoogle Scholar
  31. 31.
    Zhao M, Perry JM, Marshall H et al (2014) Megakaryocytes maintain homeostatic quiescence and promote post-injury regeneration of hematopoietic stem cells. Nat Med 20:1321–1326CrossRefPubMedGoogle Scholar
  32. 32.
    Jiang S, Levine JD, Fu Y et al (1994) Cytokine production by primary bone marrow megakaryocytes. Blood 84:4151–4156PubMedGoogle Scholar
  33. 33.
    Suzuki C, Okano A, Takatsuki F et al (1989) Continuous perfusion with interleukin 6 (IL-6) enhances production of hematopoietic stem cells (CFU-S). Biochem Biophys Res Commun 159:933–938CrossRefPubMedGoogle Scholar
  34. 34.
    Kirouac DC, Ito C, Csaszar E et al (2010) Dynamic interaction networks in a hierarchically organized tissue. Mol Syst Biol 6:417CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Choi K, Kennedy M, Kazarov A, Papadimitriou JC, Keller G (1998) A common precursor for hematopoietic and endothelial cells. Development 125:725–732PubMedGoogle Scholar
  36. 36.
    Malara A, Abbonante V, Di Buduo CA, Tozzi L, Currao M, Balduini A (2015) The secret life of a megakaryocyte: emerging roles in bone marrow homeostasis control. Cell Mol Life Sci CMLS 72:1517–1536CrossRefPubMedGoogle Scholar
  37. 37.
    Winter O, Moser K, Mohr E et al (2010) Megakaryocytes constitute a functional component of a plasma cell niche in the bone marrow. Blood 116:1867–1875CrossRefPubMedGoogle Scholar
  38. 38.
    Canton J, Schlam D, Breuer C, Gutschow M, Glogauer M, Grinstein S (2016) Calcium-sensing receptors signal constitutive macropinocytosis and facilitate the uptake of NOD2 ligands in macrophages. Nat Commun 7:11284CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Chen H, Wu L, Li Y et al (2014) Advanced glycation end products increase carbohydrate responsive element binding protein expression and promote cancer cell proliferation. Mol Cell Endocrinol 395:69–78CrossRefPubMedGoogle Scholar
  40. 40.
    Schweinfurth N, Hohmann S, Deuschle M, Lederbogen F, Schloss P (2010) Valproic acid and all trans retinoic acid differentially induce megakaryopoiesis and platelet-like particle formation from the megakaryoblastic cell line MEG-01. Platelets 21:648–657CrossRefPubMedGoogle Scholar
  41. 41.
    Nagler A, Peacock M, Tantoco M, Lamons D, Okarma TB, Okrongly DA (1993) Separation of hematopoietic progenitor cells from human umbilical cord blood. J Hematother 2:243–245CrossRefPubMedGoogle Scholar
  42. 42.
    Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63CrossRefPubMedGoogle Scholar
  43. 43.
    Chawla D, Bansal S, Banerjee BD, Madhu SV, Kalra OP, Tripathi AK (2014) Role of advanced glycation end product (AGE)-induced receptor (RAGE) expression in diabetic vascular complications. Microvasc Res 95:1–6CrossRefPubMedGoogle Scholar
  44. 44.
    Bruns I, Lucas D, Pinho S et al (2014) Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion. Nat Med 20:1315–1320CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Nakamura-Ishizu A, Takubo K, Kobayashi H, Suzuki-Inoue K, Suda T (2015) CLEC-2 in megakaryocytes is critical for maintenance of hematopoietic stem cells in the bone marrow. J Exp Med 212:2133–2146CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Norozi F, Shahrabi S, Hajizamani S, Saki N (2016) Regulatory role of megakaryocytes on hematopoietic stem cells quiescence by CXCL4/PF4 in bone marrow niche. Leuk Res 48:107–112CrossRefPubMedGoogle Scholar
  47. 47.
    Aikawa E, Fujita R, Asai M, Kaneda Y, Tamai K (2016) Receptor for advanced glycation end products-mediated signaling impairs the maintenance of bone marrow mesenchymal stromal cells in diabetic model mice. Stem Cells Dev 25:1721–1732CrossRefPubMedGoogle Scholar
  48. 48.
    Nutt SL, Metcalf D, D’Amico A, Polli M, Wu L (2005) Dynamic regulation of PU.1 expression in multipotent hematopoietic progenitors. J Exp Med 201:221–231CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Fritz G (2011) RAGE: a single receptor fits multiple ligands. Trends Biochem Sci 36:625–632CrossRefPubMedGoogle Scholar
  50. 50.
    Valencia JV, Mone M, Zhang J, Weetall M, Buxton FP, Hughes TE (2004) Divergent pathways of gene expression are activated by the RAGE ligands S100b and AGE-BSA. Diabetes 53:743–751CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Italia S.r.l., part of Springer Nature 2018

Authors and Affiliations

  • Benfang Wang
    • 1
  • Jianjiang Yu
    • 2
  • Ting Wang
    • 1
  • Ying Shen
    • 1
  • Dandan Lin
    • 1
  • Xin Xu
    • 3
  • Yiqiang Wang
    • 1
  1. 1.MOH Key Lab of Thrombosis and Hemostasis, Collaborative Innovation Center of Hematology-Thrombosis and Hemostasis Group, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhouChina
  2. 2.Department of Clinical LaboratoryThe Affiliated Jiangyin Hospital of Southeast UniversityJiangyinChina
  3. 3.Department of HematologyThe Affiliated Jiangyin Hospital of Southeast UniversityJiangyinChina

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