title: Hetrombopag, a Thrombopoietin Receptor Agonist, Protects Cardiomyocyte Survival from Oxidative Stress Damage as an Enhancer of Stem Cells.
abstract: OBJECTIVE
  Current human umbilical cord blood stem cell therapy faces the great challenges, because the stem cells are scarce and cannot survive for a long time. Here we describe how hetrombopag, an orally-active TPO receptor agonists, enhanced ex vivo expansion of human UCB stem cells, and protected cardiac myocytes from the damage caused by oxidative stress.
  
  
  METHODS
  Ex vivo expansion of stem cells were performed in serum-free medium supplemented with rhSCF and rhFL plus hetrombopag for 7 days. The percentage and number of stem cell subsets were determined by flow cytometry. Rat cardiac myocytes, ex vivo expanded stem cells, or cardiac myocytes plus ex vivo expanded stem cells were serum starved for 24 hours, and were then subjected to H2O2, hetrombopag or both for 12 hours at the indicated concentrations. Cell viability assays, protein microarrays and western blots were then performed in each group.
  
  
  RESULTS
  Our studies first revealed that the combination of hetrombopag and rhTPO manifested additive effect on ex vivo expansion of human UCB stem cells. Besides, hetrombopag dose-dependently enhanced the beneficial effects of ex vivo expanded human UCB MNCs in increasing the survival of injured cardiomyocytes during free oxygen radical stress.
  
  
  CONCLUSIONS
  These data, for the first time, uncovered a novel function of non-peptide small molecular TPO receptor agonists as enhancers of stem cells in protecting cardiac myocyte survival from oxidative stress damage, which might provide a new therapeutic avenue for the treatment of oxidative stress-related cardiovascular disease. Graphical abstract ᅟ.
authors.affiliation: Department of Geriatric Cardiology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, People's Republic of China.
authors.forename: Nannan
authors.initials: N
authors.lastname: Zhou
authors.affiliation: Department of Geriatric Cardiology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, People's Republic of China.
authors.forename: Jianchun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Geriatric Cardiology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, People's Republic of China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Geriatric Cardiology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, People's Republic of China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Geriatric Cardiology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, People's Republic of China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Cardiovascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, People's Republic of China. Chengwei_ZOU@aliyun.com.
authors.forename: Chengwei
authors.initials: C
authors.lastname: Zou
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004357:Drug Synergism; D005312:Fetal Blood / Q000166:cytology; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D020011:Protective Agents / Q000494:pharmacology; D040081:Protein Array Analysis; D047069:Pyrazolones / Q000494:pharmacology*; D000067996:RAW 264.7 Cells; D051381:Rats; D053628:Receptors, Thrombopoietin / Q000819:agonists*; D011994:Recombinant Proteins / Q000494:pharmacology; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism; D013926:Thrombopoietin / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D006835:Hydrazones; D008070:Lipopolysaccharides; D020011:Protective Agents; D047069:Pyrazolones; D053628:Receptors, Thrombopoietin; D011994:Recombinant Proteins; D013926:Thrombopoietin; C000614661:hetrombopag; D006861:Hydrogen Peroxide
keywords: Cardiac myocyte viability; Cardiovascular disease; HSC/HPCs; Hetrombopag; Oxidative stress; TPO receptor agonists