Horm Metab Res 2018; 50(04): 331-339
DOI: 10.1055/a-0588-7944
Endocrine Research
© Georg Thieme Verlag KG Stuttgart · New York

Influence of Stem Cell Therapy on Thyroid Function and Reactive Oxygen Species Production in Diabetic Rats

Diorney Luiz Souza Gran da Silva
1   Laboratory of Endocrine Physiology, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
,
Mariana Lopes de Freitas
1   Laboratory of Endocrine Physiology, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
,
Gustavo Monnerat Cahil
2   Laboratory of Cardiac Electrophysiology, IBCCF, UFRJ, Rio de Janeiro, Brazil
,
Vitória Santório de São José
2   Laboratory of Cardiac Electrophysiology, IBCCF, UFRJ, Rio de Janeiro, Brazil
,
Felippe Mousovich Neto
1   Laboratory of Endocrine Physiology, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
,
Ricardo Cortez Cardoso
1   Laboratory of Endocrine Physiology, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
,
Vânia Maria Correa da Costa
1   Laboratory of Endocrine Physiology, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
,
Rodrigo Soares Fortunato
3   Laboratory of Molecular Radiobiology, IBCCF, UFRJ, Rio de Janeiro, Brazil
,
Denise Pires de Carvalho
1   Laboratory of Endocrine Physiology, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
,
Emiliano Horácio Medei
2   Laboratory of Cardiac Electrophysiology, IBCCF, UFRJ, Rio de Janeiro, Brazil
,
Andrea Claudia Freitas Ferreira
1   Laboratory of Endocrine Physiology, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
4   Campus Duque de Caxias, NUMPEX-Bio, UFRJ, Rio de Janeiro, Brazil
› Author Affiliations
Further Information

Publication History

received 14 August 2017

accepted 01 March 2018

Publication Date:
05 April 2018 (online)

Abstract

Cell therapy with mesenchymal stem cells (MSC) has been proposed for the treatment of diabetes mellitus (DM). It is known that the prevalence of thyroid disease is higher among diabetic patients than in general population. Therefore, our aim was to investigate the effect of the treatment with MSC on thyroid function and ROS generation in an experimental model of type 1 DM. Adult male Wistar rats were divided into the following groups: control, DM (80 mg/kg BW streptozotocin, iv.) and DM+MSC. MSC treatment occurred 4 weeks after DM induction and the animals were euthanized 4 weeks after MSC administration. We also evaluated the effect of co-culture with MSC or extracellular vesicles (EV) obtained from these cells on the rat thyroid cell line PCCL3 exposed to high glucose. Thyroid H2O2 generation was increased in DM, which was reversed by MSC treatment. These changes paralled a significant DuOx1 mRNA increase. The incubation of PCCL3 with high glucose increased extracellular H2O2 generation, which was reversed by both the co-culture with MSC and EV. Even though MSC treatment normalized thyroid ROS generation, serum thyroid hormone (TH) concentration remained low, along with increased serum TSH concentrations. Thyroperoxidase (TPO) activity, was reduced in DM, and MSC treatment did not normalize TPO. Therefore, we conclude that the treatment with MSC was able to reverse the increased thyroid H2O2 generation in diabetic animals and in PCCL3 cells exposed to high glucose, an effect probably mediated by EV produced by these cells, acting in a paracrine fashion.

 
  • References

  • 1 Duntas LH, Orgiazzi J, Brabant G. The interface between thyroid and diabetes mellitus. Clin Endocrinol 2011; 75: 1-9
  • 2 Perros P, McCrimmon RJ, Shaw G, Frier BM. Frequency of thyroid dysfunction in diabetic patients: Value of annual screening. Diabet Med 1995; 12: 622-627
  • 3 Kadiyala R, Peter R, Okosieme OE. Thyroid dysfunction in patients with diabetes: Clinical Implications and Screening Strategies. Int J Clin Pract 2010; 64: 1130-1139
  • 4 Monnerat-Cahli G, Trentin-Sonoda M, Guerra B, Manso G, Ferreira AC, Silva DL, Coutinho DC, Carneiro-Ramos MS, Rodrigues DC, Cabral-da-Silva MC, Goldenberg RC, Nascimento JH, Campos de Carvalho AC, Medei E. Bone marrow mesenchymal stromal cells rescue cardiac function in streptozotocin-induced diabetic rats. Int J Cardiol 2014; 171: 199-208
  • 5 Moura EG, Pazos CC, Rosenthal D. Insulin deficiency impairs thyroid peroxidase activity. A study in experimental diabetes mellitus. Frontiers in Endocrinology. New York: Plenum Medical Book Co; 1986: 627-630
  • 6 Santos MC, Louzada RA, Souza EC, Fortunato RS, Vasconcelos AL, Souza KL, Castro JP, Carvalho DP, Ferreira AC. Diabetes mellitus increases reactive oxygen species production in the thyroid of male rats. Endocrinology 2013; 154: 1361-1372
  • 7 Larsen PR, Davies TF, Schlumberger MJ. Thyroid Physiology and Diagnostic Evaluation of Patients with Thyroid Disorders. Williams Textbook of Endocrinology. 12a edition Philadelphia: W. B. Saunders Company; 2012: 331-573
  • 8 Chen LB, Jiang XB, Yang L. Differentiation of Rat Marrow Mesenchymal Stem Cells into Pancreatic Islet Beta-Cells. World J Gastroenterol 2004; 10: 3016-3020
  • 9 Liew A, O’Brien T. The potential of cell-based therapy for diabetes and diabetes-related vascular complications. Curr Diab Rep 2014; 14: 469
  • 10 Ezquer M, Urzua CA, Montecino S, Leal K, Conget P, Ezquer F. Intravitreal administration of multipotent mesenchymal stromal cells triggers a cytoprotective microenvironment in the retina of diabetic mice. Stem Cell Res Ther 2016; 16: 7-42
  • 11 Griffin TP, Martin WP, Islam N, O'Brien T, Griffin MD. The Promise of Mesenchymal Stem Cell Therapy for Diabetic Kidney Disease. Curr Diab Rep 2016; 6: 42
  • 12 Szkudelski T. The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res 2001; 50: 537-546
  • 13 Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72: 248-254
  • 14 Fortunato RS, Lima de Souza EC, Ameziane-el Hassani R, Boufraqech M, Weyemi U, Talbot M, Lagente-Chevallier O, de Carvalho DP, Bidart JM, Schlumberger M, Dupuy C. Functional consequences of dual oxidase-thyroperoxidase interaction at the plasma membrane. J Clin Endocrinol Metab 2010; 95: 5403-5411
  • 15 Schmittgen TD, Lee EJ, Jiang J, Sarkar A, Yang L, Elton TS, Chen C. Real-time PCR quantification of precursor and mature microRNA. Methods 2008; 44: 31-38
  • 16 Ferreira AC, Lima LP, Araújo RL, Müller G, Rocha RP, Rosenthal D, Carvalho DP. Rapid regulation of thyroid sodium-iodide symporter activity by thyrotrophin and iodine. J Endocrinol 2005; 184: 69-76
  • 17 Baglio SR, Pegtel DM, Baldini N. Mesenchymal stem cell secreted vesicles provide novel opportunities in (stem) cell-free therapy. Front Physiol 2012; 3: 359
  • 18 Chazenbalk G, Magnusson RP, Rapoport B. Thyrotropin Stimulation of Cultured Thyroid Cells Increases Steady State Levels of the Messenger Ribonucleic Acid for Thyroid Peroxidase. Mol Endocrinol 1987; 1: 913-917
  • 19 Tramontano D, Cushing GW, Moses AC, Ingbar SH. Insulin-like growth factor-I stimulate the growth of rat thyroid cells in culture and synergizes the stimulation of DNA synthesis induced by TSH and Graves'-IgG. Endocrinology 1986; 119: 940-942
  • 20 Pisarev MA. Interrelationships between the pancreas and the thyroid. Curr Opin Endocrinol Diabetes Obes 2010; 17: 437-439
  • 21 Emilien G, Maloteaux JM, Ponchon M. Pharmacological management of diabetes: Recent progress and future perspective in daily drug treatment. Pharmacol Ther 1999; 81: 37-51
  • 22 Ezquer F, Ezquer M, Contador D, Ricca M, Simon V, Conget P. The antidiabetic effect of mesenchymal stem cells is unrelated to their transdifferentiation potential but to their capability to restore Th1/Th2 balance and to modify the pancreatic microenvironment. Stem Cells 2012; 30: 1664-1674
  • 23 Voltarelli JC, Couri CE, Stracieri AB, Oliveira MC, Moraes DA, Pieroni F, Coutinho M, Malmegrim KC, Foss-Freitas MC, Simões BP, Foss MC, Squiers E, Burt RK. Autologous Nonmyeloablative Hematopoietic Stem Cell Transplantation in Newly Diagnosed Type 1 Diabetes Mellitus. JAMA 2009; 302: 624
  • 24 Rigutto S, Hoste C, Dumont JE, Corvilain B, Miot F, De Deken X. Duox1 is the main source of hydrogen peroxide in the rat thyroid cell line PCCl3. Exp Cell Res 2007; 313: 3892-3901
  • 25 Sato H, Takahashi T, Sumitani K, Takatsu H, Urano S. Glucocorticoid Generates ROS to Induce Oxidative Injury in the Hippocampus, leading to Impairment of Cognitive Function of Rats. J Clin Biochem Nutr 2010; 47: 224-232
  • 26 Tang VM, Young AH, Tan H, Beasley C, Wang JF. Glucocorticoids increase protein carbonylation and mitochondrial dysfunction. Horm Metab Res 2013; 45: 709-715
  • 27 Camussi G, Deregibus MC, Bruno S, Cantaluppi V, Biancone L. Exosomes/microvesicles as a mechanism of cell-to-cell communication. Kidney Int 2010; 789: 838-848
  • 28 Kadekar D, Rangole S, Kale V, Limaye L. Conditioned Medium from Placental Mesenchymal Stem Cells Reduces Oxidative Stress during the Cryopreservation of Ex Vivo Expanded Umbilical Cord Blood Cells. PLoS One 2016; 11: e0165466
  • 29 Park CM, Kim MJ, Kim SM, Park JH, Kim ZH, Choi YS. Umbilical cord mesenchymal stem cell-conditioned media prevent muscle atrophy by suppressing muscle atrophy-related proteins and ROS generation. In Vitro Cell Dev Biol Anim 2016; 52: 68-76
  • 30 Tan X, Gong Y-Z, Wu P, Liao D-F, Zheng X-L. Mesenchymal stem cell-derived microparticles: A promising therapeutic strategy. Int J Mol Sci 2014; 15: 14348-14363
  • 31 Derkach KV, Bogush IV, Berstein LM, Shpakov AO. The influence of intranasal insulin on hypothalamic-pituitary-thyroid axis in normal and diabetic rats. Horm Metab Res 2015; 47: 916-924
  • 32 Teixeira SD, Panveloski-Costa AC, Carvalho A, Monteiro Schiavon FP, Ruiz Marque AC, Campello RS, Bazotte RB, Nunes MT. Thyroid hormone treatment decreases hepatic glucose production and renal reabsorption of glucose in alloxan-induced diabetic Wistar rats. Physiol Rep 2016 pii: e12961
  • 33 Nascimento-Saba CC, Breitenbach MM, Rosenthal D. Pituitary-thyroid axis in short- and long-term experimental diabetes mellitus. Braz J Med Biol Res 1997; 30: 269-274
  • 34 Palma CC, Pavesi M, Nogueira VG, Clemente EL, de F Vasconcellos M, Pereira Júnior LC, Pacheco FF, Braga TG, Bello Lde F, Soares JO, Dos Santos SC, Campos VP, Gomes MB. Prevalence of thyroid dysfunction in patients with diabetes mellitus. Diabetol Metab Syndr 2013; 5: 58
  • 35 Van Tienhoven-Wind LJN, Dallinga-Thie GM, Dullaart RPF. Higher plasma ApoE levels are associated with low-normal thyroid function: Studies in diabetic and nondiabetic subjects. Horm Metab Res 2016; 48: 462-467
  • 36 Mehran L, Amouzegar A, Rahimabad PK, Tohidi M, Tahmasebinejad Z, Azizi F. Thyroid function and metabolic syndrome: A population-based thyroid study. Horm Metab Res 2017; 49: 192-200
  • 37 Inan M, Bakar E, Cerkezkayabekir A, Sanal F, Ulucam E, Subaşı C, Karaöz E. Mesenchymal stem cells increase antioxidant capacity in intestinal ischemia/reperfusion damage. J Pediatr Surg 2017; 52: 1196-1206