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The current status and future of cardiac stem/progenitor cell therapy for congenital heart defects from diabetic pregnancy

Pediatric Research volume 83, pages 275282 (2018) | Download Citation

Abstract

Pregestational maternal diabetes induces congenital heart defects (CHDs). Cardiac dysfunction after palliative surgical procedures contributes to the high mortality of CHD patients. Autologous or allogeneic stem cell therapies are effective for improving cardiac function in animal models and clinical trials. c-kit+ cardiac progenitor cells (CPCs), the most recognized CPCs, have the following basic properties of stem cells: self-renewal, multicellular clone formation, and differentiation into multiple cardiac lineages. However, there is ongoing debate regarding whether c-kit+ CPCs can give rise to sufficient cardiomyocytes. A new hypothesis to address the beneficial effect of c-kit+ CPCs is that these cells stimulate endogenous cardiac cells through a paracrine function in producing a robust secretome and exosomes. The values of other cardiac CPCs, including Sca1+ CPCs and cardiosphere-derived cells, are beginning to be revealed. These cells may be better choices than c-kit+ CPCs for generating cardiomyocytes. Adult mesenchymal stem cells are considered immune-incompetent and effective for improving cardiac function. Autologous CPC therapy may be limited by the observation that maternal diabetes adversely affects the biological function of embryonic stem cells and CPCs. Future studies should focus on determining the mechanistic action of these cells, identifying new CPC markers, selecting highly effective CPCs, and engineering cell-free products.

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References

  1. 1.

    , , et al. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol 2011;58:2241–7.

  2. 2.

    , , , . Birth defects in pregestational diabetes: Defect range, glycemic threshold and pathogenesis. World J Diabetes 2015;6:481–8.

  3. 3.

    , , , . Pregestational type 2 diabetes mellitus induces cardiac hypertrophy in the murine embryo through cardiac remodeling and fibrosis. Am J Obstet Gynecol 2017;217:216.e1–13.

  4. 4.

    , , , , . Superoxide dismutase 2 overexpression alleviates maternal diabetes-induced neural tube defects, restores mitochondrial function and suppresses cellular stress in diabetic embryopathy. Free Radic Biol Med 2016;96:234–44.

  5. 5.

    , , . High glucose-induced oxidative stress represses sirtuin deacetylase expression and increases histone acetylation leading to neural tube defects. J Neurochem 2016;137:371–83.

  6. 6.

    , , , , , . New development of the yolk sac theory in diabetic embryopathy: molecular mechanism and link to structural birth defects. Am J Obstet Gynecol 2016;214:192–202.

  7. 7.

    , , , , , . Maternal diabetes triggers DNA damage and DNA damage response in neurulation stage embryos through oxidative stress. Biochem Biophys Res Commun 2015;467:407–12.

  8. 8.

    , , , . Decoding the oxidative stress hypothesis in diabetic embryopathy through proapoptotic kinase signaling. Am J Obstet Gynecol 2015;212:569–79.

  9. 9.

    , , et al. Ask1 gene deletion blocks maternal diabetes-induced endoplasmic reticulum stress in the developing embryo by disrupting the unfolded protein response signalosome. Diabetes 2015;64:973–88.

  10. 10.

    , , , , . ASK1 mediates the teratogenicity of diabetes in the developing heart by inducing ER stress and inhibiting critical factors essential for cardiac development. Am J Physiol Endocrinol Metab 2015;309:E487–99.

  11. 11.

    , , , , , . cellular stress, excessive apoptosis, and the effect of metformin in a mouse model of type 2 diabetic embryopathy. Diabetes 2015;64:2526–36.

  12. 12.

    , , . Advances in revealing the molecular targets downstream of oxidative stress-induced proapoptotic kinase signaling in diabetic embryopathy. Am J Obstet Gynecol 2015;213:125–34.

  13. 13.

    , , . Oxidative stress is responsible for maternal diabetes-impaired transforming growth factor beta signaling in the developing mouse heart. Am J Obstet Gynecol 2015;212:650.e1–11.

  14. 14.

    , , . c-Jun NH2-terminal kinase 1/2 and endoplasmic reticulum stress as interdependent and reciprocal causation in diabetic embryopathy. Diabetes 2013;62:599–608.

  15. 15.

    , , , , . Trehalose prevents neural tube defects by correcting maternal diabetes-suppressed autophagy and neurogenesis. Am J Physiol Endocrinol Metab 2013;305:E667–78.

  16. 16.

    , , , . SOD1 suppresses maternal hyperglycemia-increased iNOS expression and consequent nitrosative stress in diabetic embryopathy. Am J Obstet Gynecol 2012;206:e441–7.

  17. 17.

    , , , . SOD1 overexpression in vivo blocks hyperglycemia-induced specific PKC isoforms: substrate activation and consequent lipid peroxidation in diabetic embryopathy. Am J Obstet Gynecol 2011;205:e81–6.

  18. 18.

    , , et al. Protein kinase C-alpha suppresses autophagy and induces neural tube defects via miR-129-2 in diabetic pregnancy. Nat Commun 2017;8:15182.

  19. 19.

    , , , , . Endoplasmic reticulum stress-induced CHOP inhibits PGC-1alpha and causes mitochondrial dysfunction in diabetic embryopathy. Toxicol Sci 2017;158:275–85.

  20. 20.

    , , et al. Diabetes mellitus and birth defects. Am J Obstet Gynecol 2008;199:e231–9.

  21. 21.

    , , . Cardiovascular malformations in infants of diabetic mothers. Heart 2003;89:1217–20.

  22. 22.

    , , , , . Mortality resulting from congenital heart disease among children and adults in the United States, 1999 to 2006. Circulation 2010;122:2254–63.

  23. 23.

    , , , , . Late causes of death after pediatric cardiac surgery: a 60-year population-based study. J Am Coll Cardiol 2016;68:487–98.

  24. 24.

    , , et al. Mortality in adult congenital heart disease. Eur Heart J 2010;31:1220–9.

  25. 25.

    , , et al. Heart failure admissions in adults with congenital heart disease; risk factors and prognosis. Int J Cardiol 2013;168:2487–93.

  26. 26.

    , , , , . High glucose suppresses embryonic stem cell differentiation into cardiomyocytes: high glucose inhibits ES cell cardiogenesis. Stem Cell Res Ther 2016;7:187.

  27. 27.

    , , . Diabetes-induced effects on cardiomyocytes in chick embryonic heart micromass and mouse embryonic D3 differentiated stem cells. Reprod Toxicol 2017;69:242–53.

  28. 28.

    , , , , , . Maternal diabetes and high glucose in vitro trigger Sca1+ cardiac progenitor cell apoptosis through FoxO3a. Biochem Biophys Res Commun 2017;482:575–81.

  29. 29.

    , . Stem-cell therapy for cardiac disease. Nature 2008;451:937–42.

  30. 30.

    . Cell therapy trials in congenital heart disease. Circ Res 2017;120:1353–66.

  31. 31.

    , , , , . Organ allocation in adults with congenital heart disease listed for heart transplant: impact of ventricular assist devices. J Heart Lung Transplant 2013;32:1059–64.

  32. 32.

    , , et al. The effect of age, diagnosis, and previous surgery in children and adults undergoing heart transplantation for congenital heart disease. J Am Coll Cardiol 2009;54:160–5.

  33. 33.

    , , et al. Transplantation and mechanical circulatory support in congenital heart disease: a scientific statement from the American Heart Association. Circulation 2016;133:802–20.

  34. 34.

    , , . Past and present of cardiocirculatory assist devices: a comprehensive critical review. J Geriatr Cardiol 2012;9:389–400.

  35. 35.

    , , et al. A comparative analysis of the results from 4 trials of beta-blocker therapy for heart failure: BEST, CIBIS-II, MERIT-HF, and COPERNICUS. J Card Fail 2003;9:354–63.

  36. 36.

    SOLVD InvestigatorsSOLVD Investigators SOLVD Investigators SOLVD Investigators SOLVD Investigators SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293–302.

  37. 37.

    , . Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). Am J Cardiol 1988;62:60A–66A.

  38. 38.

    , , et al. Carvedilol for children and adolescents with heart failure: a randomized controlled trial. JAMA 2007;298:1171–9.

  39. 39.

    , , et al. Enalapril in infants with single ventricle: results of a multicenter randomized trial. Circulation 2010;122:333–40.

  40. 40.

    , , et al. Angiotensin receptor blockade and exercise capacity in adults with systemic right ventricles: a multicenter, randomized, placebo-controlled clinical trial. Circulation 2005;112:2411–6.

  41. 41.

    , , et al. N-acetylcysteine prevents congenital heart defects induced by pregestational diabetes. Cardiovasc Diabetol 2014;13:46.

  42. 42.

    , , , , , . The total artificial heart: where we stand. Cardiology 2004;101:117–21.

  43. 43.

    , . The emergence of stem cell therapy for patients with congenital heart disease. Circ Res 2015;116:566–9.

  44. 44.

    , , . Stem-cell-based therapy and lessons from the heart. Nature 2008;453:322–9.

  45. 45.

    , , et al. Rescue of neonatal cardiac dysfunction in mice by administration of cardiac progenitor cells in utero. Nat Commun 2015;6:8825.

  46. 46.

    , , et al. Dynamics of cell generation and turnover in the human heart. Cell 2015;161:1566–75.

  47. 47.

    , , et al. Oncostatin M is a major mediator of cardiomyocyte dedifferentiation and remodeling. Cell Stem Cell 2011;9:420–32.

  48. 48.

    , , et al. Noncultured cell transplantation in an ovine model of right ventricular preparation. J Thorac Cardiovasc Surg 2005;129:1119–27.

  49. 49.

    , , et al. Skeletal myoblast sheet transplantation improves the diastolic function of a pressure-overloaded right heart. J Thorac Cardiovasc Surg 2009;138:460–7.

  50. 50.

    , , et al. Safety and feasibility for pediatric cardiac regeneration using epicardial delivery of autologous umbilical cord blood-derived mononuclear cells established in a porcine model system. Stem Cells Transl Med 2015;4:195–206.

  51. 51.

    , , et al. Human cord blood stem cells enhance neonatal right ventricular function in an ovine model of right ventricular training. Ann Thorac Surg 2010;89:585–93 593.e1–4.

  52. 52.

    , , et al. Myocyte turnover in the aging human heart. Circ Res 2010;107:1374–86.

  53. 53.

    , , et al. Human cardiac stem cells. Proc Natl Acad Sci USA 2007;104:14068–73.

  54. 54.

    , , et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 2003;114:763–776.

  55. 55.

    , , et al. Cardiomyogenesis in the developing heart is regulated by c-kit-positive cardiac stem cells. Circ Res 2012;110:701–15.

  56. 56.

    , , et al. c-kit expression identifies cardiovascular precursors in the neonatal heart. Proc Natl Acad Sci USA 2009;106:1808–13.

  57. 57.

    , , , . Cardiomyogenic potential of C-kit(+)-expressing cells derived from neonatal and adult mouse hearts. Circulation 2010;121:1992–2000.

  58. 58.

    , , et al. c-kit+ cells minimally contribute cardiomyocytes to the heart. Nature 2014;509:337–41.

  59. 59.

    , , et al. Resident c-kit(+) cells in the heart are not cardiac stem cells. Nat Commun 2015;6:8701.

  60. 60.

    , , et al. Dissecting the molecular relationship among various cardiogenic progenitor cells. Circ Res 2013;112:1253–62.

  61. 61.

    , , et al. Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc Natl Acad Sci USA 2003;100:12313–8.

  62. 62.

    , , et al. Human cardiomyocyte progenitor cell transplantation preserves long-term function of the infarcted mouse myocardium. Cardiovasc Res 2009;83:527–35.

  63. 63.

    , , et al. Progenitor cells isolated from the human heart: a potential cell source for regenerative therapy. Neth Heart J 2008;16:163–9.

  64. 64.

    , , et al. Sca1-derived cells are a source of myocardial renewal in the murine adult heart. Stem Cell Rep 2013;1:397–410.

  65. 65.

    , , . Resveratrol activates endogenous cardiac stem cells and improves myocardial regeneration following acute myocardial infarction. Mol Med Rep 2017;15:1188–94.

  66. 66.

    , , et al. Sca-1 knockout impairs myocardial and cardiac progenitor cell function. Circ Res 2012;111:750–60.

  67. 67.

    , , et al. Sca-1+ cardiac progenitor cell therapy with cells overexpressing integrin-linked kinase improves cardiac function after myocardial infarction. Transplantation 2013;95:1187–96.

  68. 68.

    , , et al. Intrinsic cardiac origin of human cardiosphere-derived cells. Eur Heart J 2013;34:68–75.

  69. 69.

    , , et al. Human cardiac stem cells exhibit mesenchymal features and are maintained through Akt/GSK-3beta signaling. Biochem Biophys Res Commun 2007;352:635–41.

  70. 70.

    , , et al. Relative roles of direct regeneration versus paracrine effects of human cardiosphere-derived cells transplanted into infarcted mice. Circ Res 2010;12010:971–80.

  71. 71.

    , , et al. Safety and efficacy of allogeneic cell therapy in infarcted rats transplanted with mismatched cardiosphere-derived cells. Circulation 2012;125:100–12.

  72. 72.

    , , et al. Validation of contrast-enhanced magnetic resonance imaging to monitor regenerative efficacy after cell therapy in a porcine model of convalescent myocardial infarction. Circulation 2013;128:2764–75.

  73. 73.

    , , , . Developmental origin and lineage plasticity of endogenous cardiac stem cells. Development 2016;143:1242–58.

  74. 74.

    , . Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease. Circ Res 2011;109:923–40.

  75. 75.

    , , et al. Mesenchymal stem cells preserve neonatal right ventricular function in a porcine model of pressure overload. Am J Physiol Heart Circ Physiol 2016;310:H1816–26.

  76. 76.

    , . Cardiac progenitor cells for heart repair. Cell Death Discov 2016;2:16052.

  77. 77.

    , , . Mesenchymal stem cells in cardiac regeneration: a detailed progress report of the last 6 years (2010-2015). Stem Cell Res Ther 2016;7:82.

  78. 78.

    , , et al. Potential risks of bone marrow cell transplantation into infarcted hearts. Blood 2007;110:1362–9.

  79. 79.

    , , , , . Intracoronary infusion of skeletal myoblasts improves cardiac function in doxorubicin-induced heart failure. Circulation 2001;104:I213–7.

  80. 80.

    , , et al. Does the functional efficacy of skeletal myoblast transplantation extend to nonischemic cardiomyopathy? Circulation 2004;110:1626–31.

  81. 81.

    , , et al. Transplantation of mesenchymal stem cells improves cardiac function in a rat model of dilated cardiomyopathy. Circulation 2005;112:1128–35.

  82. 82.

    , , et al. Mesenchymal stem cell transplantation attenuates cardiac fibrosis associated with isoproterenol-induced global heart failure. Transpl Int 2008;21:1181–9.

  83. 83.

    , , et al. Anthracycline cardiomyopathy is mediated by depletion of the cardiac stem cell pool and is rescued by restoration of progenitor cell function. Circulation 2010;121:276–92.

  84. 84.

    , , et al. Therapeutic efficacy of cardiosphere-derived cells in a transgenic mouse model of non-ischaemic dilated cardiomyopathy. Eur Heart J 2015;36:751–62.

  85. 85.

    , , , , , . Human umbilical cord blood derived mesenchymal stem cells improve cardiac function in cTnT(R141W) transgenic mouse of dilated cardiomyopathy. Eur J Cell Biol 2016;95:57–67.

  86. 86.

    , , et al. Controlled delivery of basic fibroblast growth factor promotes human cardiosphere-derived cell engraftment to enhance cardiac repair for chronic myocardial infarction. J Am Coll Cardiol 2008;52:1858–65.

  87. 87.

    , , et al. Engraftment, differentiation, and functional benefits of autologous cardiosphere-derived cells in porcine ischemic cardiomyopathy. Circulation 2009;120:1077–83 7 p following 1083.

  88. 88.

    , , et al. Intracoronary delivery of autologous cardiac stem cells improves cardiac function in a porcine model of chronic ischemic cardiomyopathy. Circulation 2013;128:122–31.

  89. 89.

    , , et al. c-kit+ Cardiac stem cells alleviate post-myocardial infarction left ventricular dysfunction despite poor engraftment and negligible retention in the recipient heart. PLoS ONE 2014;9:e96725.

  90. 90.

    , , , . Proangiogenic features of mesenchymal stem cells and their therapeutic applications. Stem Cells Int 2016;2016:1314709.

  91. 91.

    , , et al. Mesenchymal stem cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a canine chronic ischemia model. Circulation 2005;111:50–156.

  92. 92.

    , , , , . Endothelial cells promote cardiac myocyte survival and spatial reorganization: implications for cardiac regeneration. Circulation 2004;110:962–8.

  93. 93.

    , . Cell-based approaches for cardiac repair. Ann NY Acad Sci 2006;1080:34–48.

  94. 94.

    , , et al. Stimulation of endogenous cardioblasts by exogenous cell therapy after myocardial infarction. EMBO Mol Med 2014;6:760–77.

  95. 95.

    , , et al. Direct comparison of different stem cell types and subpopulations reveals superior paracrine potency and myocardial repair efficacy with cardiosphere-derived cells. J Am Coll Cardiol 2012;59:942–53.

  96. 96.

    , , et al. Implantation of mesenchymal stem cells improves right ventricular impairments caused by experimental pulmonary hypertension. Am J Med Sci 2012;343:402–6.

  97. 97.

    , , , . Mesenchymal stem cell-conditioned media suppresses inflammation-associated overproliferation of pulmonary artery smooth muscle cells in a rat model of pulmonary hypertension. Exp Ther Med 2016;11:467–75.

  98. 98.

    , . An emerging consensus on cardiac regeneration. Nat Med 2014;20:1386–93.

  99. 99.

    , , . Exosomes as critical agents of cardiac regeneration triggered by cell therapy. Stem Cell Rep 2014;2:606–19.

  100. 100.

    , , , . Stem cell exosomes as cell-free modality for cardiac repair. Circ Res 2016;118:330–43.

  101. 101.

    , , et al. A deep proteome analysis identifies the complete secretome as the functional unit of human cardiac progenitor cells. Circ Res 2017;120:816–34.

  102. 102.

    , , , , , . Exosomes as intercellular signaling organelles involved in health and disease: basic science and clinical applications. Int J Mol Sci 2013;14:5338–66.

  103. 103.

    , . Intercellular communication by exosome-derived microRNAs in cancer. Int J Mol Sci 2013;14:14240–69.

  104. 104.

    , , et al. Experimental, systems, and computational approaches to understanding the microRNA-mediated reparative potential of cardiac progenitor cell-derived exosomes from pediatric patients. Circ Res 2017;120:701–12.

  105. 105.

    , , et al. Exosomes secreted by cardiosphere-derived cells reduce scarring, attenuate adverse remodelling, and improve function in acute and chronic porcine myocardial infarction. Eur Heart J 2017;38:201–11.

  106. 106.

    , , et al. Cardiosphere-derived cells from pediatric end-stage heart failure patients have enhanced functional activity due to the heat shock response regulating the secretome. Stem Cells 2015;33:1213–29.

  107. 107.

    , , et al. Pediatric end-stage failing hearts demonstrate increased cardiac stem cells. Ann Thorac Surg 2015;100:615–22.

  108. 108.

    , . Strategies and challenges to myocardial replacement therapy. Stem Cells Transl Med 2016;5:410–6.

  109. 109.

    , , et al. 3D printed complex tissue construct using stem cell-laden decellularized extracellular matrix bioinks for cardiac repair. Biomaterials 2017;112:264–74.

  110. 110.

    , , et al. Intracoronary administration of autologous bone marrow-derived progenitor cells in a critically ill two-yr-old child with dilated cardiomyopathy. Pediatr Transplant 2009;13:620–3.

  111. 111.

    , , et al. Intracoronary bone marrow cell application for terminal heart failure in children. Cardiol Young 2012;22:558–63.

  112. 112.

    , , et al. A regenerative strategy for heart failure in hypoplastic left heart syndrome: intracoronary administration of autologous bone marrow-derived progenitor cells. J Heart Lung Transplant 2010;29:574–7.

  113. 113.

    , , , , . Follow-up of the patients after stem cell transplantation for pediatric dilated cardiomyopathy. Pediatr Transplant 2013;17:266–70.

  114. 114.

    , , et al. Intracoronary autologous cardiac progenitor cell transfer in patients with hypoplastic left heart syndrome: the TICAP prospective phase 1 controlled trial. Circ Res 2015;116:653–64.

  115. 115.

    , , et al. Intracoronary cardiac progenitor cells in single ventricle physiology: the PERSEUS (Cardiac Progenitor Cell Infusion to Treat Univentricular Heart Disease) randomized phase 2 trial. Circ Res 2017;120:1162–73.

  116. 116.

    , , . Challenges to success in heart failure: cardiac cell therapies in patients with heart diseases. J Cardiol 2016;68:361–7.

  117. 117.

    , , et al. Umbilical cord mesenchymal stromal cells affected by gestational diabetes mellitus display premature aging and mitochondrial dysfunction. Stem Cells Dev 2015;24:575–86.

  118. 118.

    , . Stem cell therapy for cardiac repair. J Cardiovasc Nurs 2009;24:93–7.

  119. 119.

    , , , , , . microRNA expression profiling and functional annotation analysis of their targets modulated by oxidative stress during embryonic heart development in diabetic mice. Reprod Toxicol 2016;65:365–74.

  120. 120.

    , , . MiR-17 downregulation by high glucose stabilizes thioredoxin-interacting protein and removes thioredoxin inhibition on ASK1 leading to apoptosis. Toxicol Sci 2016;150:84–96.

  121. 121.

    , , et al. High glucose-repressed CITED2 expression through miR-200b triggers the unfolded protein response and endoplasmic reticulum stress. Diabetes 2016;65:149–63.

  122. 122.

    , , , , , . The miR-322-TRAF3 circuit mediates the pro-apoptotic effect of high glucose on neural stem cells. Toxicol Sci 2015;144:186–96.

  123. 123.

    . MicroRNAs: target recognition and regulatory functions. Cell 2009;136:215–33.

  124. 124.

    , , et al. Functional screening identifies miRNAs inducing cardiac regeneration. Nature 2012;492:376–81.

  125. 125.

    , , et al. Therapeutic inhibition of miR-208a improves cardiac function and survival during heart failure. Circulation 2011;124:1537–47.

  126. 126.

    , , et al. Role of miR-21 in the pathogenesis of atrial fibrosis. Basic Res Cardiol 2012;107:278.

  127. 127.

    , . Function and therapeutic potential of noncoding RNAs in cardiac fibrosis. Circ Res 2016;118:108–18.

  128. 128.

    , , . Toward microRNA-based therapeutics for heart disease: the sense in antisense. Circ Res 2008;103:919–28.

  129. 129.

    , . MicroRNA therapeutics for cardiovascular disease: opportunities and obstacles. Nat Rev Drug Discov 2012;11:860–72.

  130. 130.

    , . Long noncoding RNAs in cardiovascular diseases. Circ Res 2015;116:737–50.

  131. 131.

    , , , . MicroRNAs in congenital heart disease. Ann Transl Med 2015;3:333.

  132. 132.

    , , et al. MicroRNA 210 as a biomarker for congestive heart failure. Biol Pharm Bull 2013;36:48–54.

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Affiliations

  1. Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland

    • Jianxiang Zhong
    • , Shengbing Wang
    • , Wei-Bin Shen
    •  & Peixin Yang
  2. Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland

    • Sunjay Kaushal
  3. Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland

    • Peixin Yang

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The authors declare no conflict of interest.

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Correspondence to Peixin Yang.

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https://doi.org/10.1038/pr.2017.259

Statement of Financial Support

This work is supported by the NIH grants NIH R01DK083243, R01DK101972, R01HL131737, R01HL134368, R01HL139060, and R01DK103024.