An update of human mesenchymal stem cell biology and their clinical uses

Archives of Toxicology

Volumn 88, Issue 5, 2014, Pages 1069-1082

  Zaher, Walid ^a,c   Harkness, Linda ^a   Jafari, Abbas ^a,b   Kassem, Moustapha ^a,b,c  

^a ODENSE UNIVERSITY HOSPITAL   (Denmark)

^b University of Copenhagen   (Denmark)

^c KING SAUD UNIVERSITY   (Saudi Arabia)

Author keywords

Adipogenesis; Bone; Osteogenesis; Regenerative medicine; Stromal stem cells

Indexed keywords

ACTIVATING TRANSCRIPTION FACTOR 4; BETA CATENIN; TRANSCRIPTION FACTOR AP 1; TRANSCRIPTION FACTOR MSX1; TRANSCRIPTION FACTOR OSTERIX; TRANSCRIPTION FACTOR RUNX2; TRANSCRIPTION FACTOR SOX9;

ADIPOCYTE; AUTOLOGOUS STEM CELL TRANSPLANTATION; BONE DEVELOPMENT; CARTILAGE CELL; CELL DIFFERENTIATION; CELL FUNCTION; CELL ISOLATION; CLINICAL EFFECTIVENESS; CLINICAL MEDICINE; CYTOLOGY; GRAFT VERSUS HOST REACTION; HEART INFARCTION; HEART MUSCLE REGENERATION; HUMAN; HUMAN CELL; MESENCHYMAL STEM CELL; MESENCHYMAL STEM CELL TRANSPLANTATION; MESENCHYMAL STROMA CELL; OSTEOBLAST; PATIENT SAFETY; PLURIPOTENT STEM CELL; PRIORITY JOURNAL; REGULATORY MECHANISM; REVIEW; TISSUE REGENERATION; PHYSIOLOGY; REGENERATION; STEM CELL TRANSPLANTATION;

ADIPOCYTES; CELL DIFFERENTIATION; CHONDROCYTES; GRAFT VS HOST DISEASE; HUMANS; MESENCHYMAL STROMAL CELLS; OSTEOBLASTS; PLURIPOTENT STEM CELLS; REGENERATION; STEM CELL TRANSPLANTATION;

EID: 84901328262     PISSN: 03405761     EISSN: 14320738     Source Type: Journal    
DOI: 10.1007/s00204-014-1232-8     Document Type: Review

References (189)

1. Abdallah Basem M, Harkness L, Mahmood A, Kassem M (2011) Direct differentiation of human embryonic stem cells toward osteoblasts and chondrocytes through an intermediate mesenchyme progenitor lineage. In: Atwood C (ed) Embryonic stem cells: the hormonal regulation of pluripotency and embryogenesis, InTech Europe, Rijeka, Croatia, p 607-618. http://www.intechopen. com
2. Akiyama H, Lefebvre V (2011) Unraveling the transcriptional regulatory machinery in chondrogenesis. J Bone Miner Metab 29(4):390-395. doi:10.1007/s00774-011-0273-9
3. Al-Nbaheen M, Vishnubalaji R, Ali D et al (2013) Human stromal (mesenchymal) stem cells from bone marrow, adipose tissue and skin exhibit differences in molecular phenotype and differentiation potential. Stem Cell Rev 9(1):32-43. doi:10.1007/s12015-012-9365-8
4. Barberi T, Willis LM, Socci ND, Studer L (2005) Derivation of multipotent mesenchymal precursors from human embryonic stem cells. PLoS Med 2(6):e161
5. Barbuto R, Mitchell J (2013) Regulation of the osterix (Osx, Sp7) promoter by osterix and its inhibition by parathyroid hormone. J Mol Endocrinol 51(1):99-108. doi:10.1530/JME-12-0251
6. Bentivegna AMM, Riva G, Foudah D, Butta V, Dalprà L, Tredici G (2013) DNA methylation changes during in vitro propagation of human mesenchymal stem cells: implications for their genomic stability? Stem Cells Int 2013:192425. doi:10.1155/2013/192425
7. Bentzon JF, Stenderup K, Hansen FD et al (2005) Tissue distribution and engraftment of human mesenchymal stem cells immortalized by human telomerase reverse transcriptase gene. Biochem Biophys Res Commun 330(3):633-640. doi:10.1016/j.bbrc.2005.03.072 (Pubitemid 40462134)
8. Bhansali A, Upreti V, Khandelwal N et al (2009) Efficacy of autologous bone marrow-derived stem cell transplantation in patients with type 2 diabetes mellitus. Stem Cells Dev 18(10):1407-1416. doi:10.1089/scd.2009.0164
9. Bianco P, Riminucci M, Gronthos S, Robey PG (2001) Bone marrow stromal stem cells: nature, biology, and potential applications. Stem Cells 19(3):180-192 (Pubitemid 32524539)
10. Bianco P, Kuznetsov SA, Riminucci M, Gehron RP (2006) Postnatal skeletal stem cells. Methods Enzymol 419:117-148 (Pubitemid 44820365)
11. Bianco P, Cao X, Frenette PS et al (2013) The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat Med 19(1):35-42. doi:10.1038/nm.3028
12. Bieberich E, Silva J, Wang G, Krishnamurthy K, Condie BG (2004) Selective apoptosis of pluripotent mouse and human stem cells by novel ceramide analogues prevents teratoma formation and enriches for neural precursors in ES cell-derived neural transplants. J Cell Biol 167(4):723-734 (Pubitemid 39565152)
13. Borengasser SJ, Zhong Y, Kang P et al (2013) Maternal obesity enhances white adipose tissue differentiation and alters genome-scale DNA methylation in male rat offspring. Endocrinology 154(11):4113-4125. doi:10.1210/en.2012-2255
14. Boyd NL, Robbins KR, Dhara SK, West FD, Stice SL (2009) Human embryonic stem cell-derived mesoderm-like epithelium transitions to mesenchymal progenitor cells. Tissue Eng Part A 15(8):1897-1907
15. Brown SE, Tong W, Krebsbach PH (2009) The derivation of mesenchymal stem cells from human embryonic stem cells. Cells Tissues Organs 189(1-4):256-260
16. Caplan AI (1991) Mesenchymal stem cells. J Orthop Res Off Publ Orthop Res Soc 9(5):641-650. doi:10.1002/jor.1100090504
17. Chen SL, Fang W, Ye F et al (2004) Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am J Cardiol 94(1):92-95 (Pubitemid 38813459)
18. Chen S, Tao J, Bae Y et al (2013) Notch gain of function inhibits chondrocyte differentiation via Rbpj-dependent suppression of Sox9. J Bone Miner Res Off J Am Soc Bone Miner Res 28(3):649-659. doi:10.1002/jbmr.1770
19. Choi H, Lee RH, Bazhanov N, Oh JY, Prockop DJ (2011a) Anti-inflammatory protein TSG-6 secreted by activated MSCs attenuates zymosan-induced mouse peritonitis by decreasing TLR2/NF-kappaB signaling in resident macrophages. Blood 118(2):330-338. doi:10.1182/blood-2010-12-327353
20. Choi YH, Gu YM, Oh JW, Lee KY (2011b) Osterix is regulated by Erk1/2 during osteoblast differentiation. Biochem Biophy Res Commun 415(3):472-478. doi:10.1016/j.bbrc.2011.10.097
21. Choi YH, Jeong HM, Jin YH, Li H, Yeo CY, Lee KY (2011c) Akt phosphorylates and regulates the osteogenic activity of Osterix. Biochem Biophys Res Commun 411(3):637-641. doi:10.1016/j.bbrc.2011.07.009
22. Choi YH, Choi JH, Oh JW, Lee KY (2013) Calmodulin-dependent kinase II regulates osteoblast differentiation through regulation of Osterix. Biochem Biophys Res Commun 432(2):248-255. doi:10.1016/j.bbrc.2013.02.005
23. Cook D, Genever P (2013) Regulation of mesenchymal stem cell differentiation. Adv Exp Med Biol 786:213-229. doi:10.1007/978-94-007-6621-1-12
24. Cunningham JJ, Ulbright TM, Pera MF, Looijenga LHJ (2012) Lessons from human teratomas to guide development of safe stem cell therapies. Nat Biotech 30(9):849-857
25. Dai L, Zhang X, Hu X, Zhou C, Ao Y (2012) Silencing of micro-RNA-101 prevents IL-1beta-induced extracellular matrix degradation in chondrocytes. Arthritis Res Ther 14(6):R268. doi:10.1186/ar4114
26. Database UNIoHNctrar In. (2014) http://clinicaltrials.gov/ Accessed 6 February 2014
27. De Miguel MP, F-JS Blázquez-Martínez A, Pascual CY, Aller MA, Arias J, Arnalich-Montiel F (2012) Immunosuppressive properties of mesenchymal stem cells: advances and applications. Curr Mol Med 12(5):17. doi:10.2174/156652412800619950
28. de Peppo GM, Sjovall P, Lennerås M, et al (2010) osteogenic potential of human mesenchymal stem cells and human embryonic stem cell-derived mesodermal progenitors: a tissue engineering perspective. Tissue Eng Part A 16(11). doi: 10.1089/ten.tea.2010.0052
29. Devine SM, Bartholomew AM, Mahmud N et al (2001) Mesenchymal stem cells are capable of homing to the bone marrow of non-human primates following systemic infusion. Exp Hematol 29(2):244-255
30. Diederichsen AC, Moller JE, Thayssen P et al (2010) Changes in left ventricular filling patterns after repeated injection of autologous bone marrow cells in heart failure patients. Scand Cardiovasc J 44(3):139-145. doi:10.3109/14017430903556294
31. Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G (1997) Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 89(5):747-754 (Pubitemid 27516177)
32. Duijvestein M, Vos AC, Roelofs H et al (2010) Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn's disease: results of a phase I study. Gut 59(12):1662-1669. doi:10.1136/gut. 2010.215152
33. Eskildsen T, Taipaleenmaki H, Stenvang J et al (2011) Micro-RNA-138 regulates osteogenic differentiation of human stromal (mesenchymal) stem cells in vivo. Proc Natl Acad Sci USA 108(15):6139-6144. doi:10.1073/pnas.1016758108
34. Estrada EJ, Valacchi F, Nicora E et al (2008) Combined treatment of intrapancreatic autologous bone marrow stem cells and hyperbaric oxygen in type 2 diabetes mellitus. Cell Transpl 17(12):1295-1304
35. Evseenko D, Zhu Y, Schenke-Layland K et al (2010) Mapping the first stages of mesoderm commitment during differentiation of human embryonic stem cells. Proc Natl Acad Sci 107(31):13742-13747
36. Fajas L, Schoonjans K, Gelman L et al (1999) Regulation of peroxisome proliferator-activated receptor gamma expression by adipocyte differentiation and determination factor 1/sterol regulatory element binding protein 1: implications for adipocyte differentiation and metabolism. Mol Cell Biol 19(8):5495-5503 (Pubitemid 29339907)
37. Fang B, Song Y, Lin Q et al (2007) Human adipose tissue-derived mesenchymal stromal cells as salvage therapy for treatment of severe refractory acute graft-vs.-host disease in two children. Pediatr Transpl 11(7):814-817 (Pubitemid 47512333)
38. Fengming Yue SS, Ichikawa H, Yoshie S, Akimi Mogi SM, Nagai M, Yokohama T, Sasaki TDaK (2013) Induce differentiation of embryonic stem cells by co-culture system. In: Andrades PJA (ed) Regenerative medicine and tissue engineering. InTech Europe, Rijeka, Croatia, p 117-139. http://www.intechopen. com
39. Fischer-Rasokat U, Assmus B, Seeger FH et al (2009) A pilot trial to assess potential effects of selective intracoronary bone marrow-derived progenitor cell infusion in patients with nonischemic dilated cardiomyopathy: final 1-year results of the transplantation of progenitor cells and functional regeneration enhancement pilot trial in patients with nonischemic dilated cardiomyopathy. Circ Heart Fail 2(5):417-423. doi:10.1161/CIRCHEART FAILURE.109.855023
40. Franceschi RT, Xiao G, Jiang D, Gopalakrishnan R, Yang S, Reith E (2003) Multiple signaling pathways converge on the Cbfa1/Runx2 transcription factor to regulate osteoblast differentiation. Connect Tissue Res 44(Suppl 1):109-116 (Pubitemid 36395431)
41. Franceschi RT, Ge C, Xiao G, Roca H, Jiang D (2007) Transcriptional regulation of osteoblasts. Ann N Y Acad Sci 1116:196-207. doi:10.1196/annals. 1402.081 (Pubitemid 350274351)
42. Freytag SO, Paielli DL, Gilbert JD (1994) Ectopic expression of the CAAT/enhancer-binding protein alpha promotes the adipogenic program in a variety of mouse fibroblastic cells. Genes Dev 8(14):1654-1663 (Pubitemid 24236244)
43. Friedenstein AJ, Piatetzky S II, Petrakova KV (1966) Osteogenesis in transplants of bone marrow cells. J Embryol Exp Morphol 16(3):381-390
44. Friedenstein AJ, Chailakhyan RK, Gerasimov UV (1987) Bone marrow osteogenic stem cells: in vitro cultivation and transplantation in diffusion chambers. Cell Tissue Kinet 20(3):263-272
45. Fujita T, Azuma Y, Fukuyama R et al (2004) Runx2 induces osteoblast and chondrocyte differentiation and enhances their migration by coupling with PI3 K-Akt signaling. J Cell Biol 166(1):85-95. doi:10.1083/jcb.200401138 (Pubitemid 38931919)
46. Fuster V, Kelly BB, Vedanthan R (2011) Global cardiovascular health: urgent need for an intersectoral approach. J Am Coll Cardiol 58(12):1208-1210
47. Gamez B, Rodriguez-Carballo E, Bartrons R, Rosa JL, Ventura F (2013) MicroRNA-322 (miR-322) and its target protein Tob2 modulate Osterix (Osx) mRNA stability. J Biol Chem 288(20):14264-14275. doi:10.1074/jbc.M112.432104
48. Gangji V, Hauzeur JP (2005) Treatment of osteonecrosis of the femoral head with implantation of autologous bone-marrow cells. Surgical technique. J Bone Joint Surg Am 87(Suppl 1 Pt 1):106-112. doi:10.2106/JBJS.D.02662 (Pubitemid 40315042)
49. Gimble JM, Robinson CE, Wu X et al (1996) Peroxisome proliferator- activated receptor-gamma activation by thiazolidinediones induces adipogenesis in bone marrow stromal cells. Mol Pharmacol 50(5):1087-1094 (Pubitemid 26384846)
50. Gnecchi M, Zhang Z, Ni A, Dzau VJ (2008) Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res 103(11):1204-1219. doi:10.1161/CIRCRESAHA.108.176826
51. Goettsch C, Rauner M, Pacyna N, Hempel U, Bornstein SR, Hofbauer LC (2011) miR-125b regulates calcification of vascular smooth muscle cells. Am J Pathol 179(4):1594-1600. doi:10.1016/j.ajpath.2011.06.016
52. Gu S, Boyer TG, Naski MC (2012) Basic helix-loop-helix transcription factor Twist1 inhibits transactivator function of master chondrogenic regulator Sox9. J Biol Chem 287(25):21082-21092. doi:10.1074/jbc.M111.328567
53. Hagenkord J, Parwani A, Lyons-Weiler M et al (2008) Virtual karyotyping with SNP microarrays reduces uncertainty in the diagnosis of renal epithelial tumors. Diagn Pathol 3(1):44
54. Haider HK, Jiang S, Idris NM, Ashraf M (2008) IGF-1-over-expressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of SDF-1alpha/CXCR4 signaling to promote myocardial repair. Circ Res 103(11):1300-1308
55. Hare JM, Traverse JH, Henry TD et al (2009) A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol 54(24):2277-2286
56. Harkness L, Mahmood A, Ditzel N, Abdallah BM, Nygaard JV, Kassem M (2010) Selective isolation and differentiation of a stromal population of human embryonic stem cells with osteogenic potential. Bone 48(2):231-241. doi:10.1016/j.bone.2010.09.023
57. Harkness L, Mahmood A, Ditzel N, Abdallah BM, Nygaard JV, Kassem M (2011) Selective isolation and differentiation of a stromal population of human embryonic stem cells with osteogenic potential. Bone 48(2):231-241
58. Harkness LNS, Beermann J, Bozhevolnyi SI, Kassem M (2012) Identification of abnormal stem cells using Raman spectroscopy. Stem Cells Dev 21(12):8. doi:10.1089/scd.2011.0600
59. Hata K, Takashima R, Amano K et al (2013) Arid5b facilitates chondrogenesis by recruiting the histone demethylase Phf2 to Sox9-regulated genes. Nat Commun 4:2850. doi:10.1038/ncomms3850
60. Hatzistergos KE, Quevedo H, Oskouei BN et al (2010) Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circ Res 107(7):913-922. doi:10.1161/CIRCRESAHA.110.222703
61. Heile AM, Wallrapp C, Klinge PM et al (2009) Cerebral transplantation of encapsulated mesenchymal stem cells improves cellular pathology after experimental traumatic brain injury. Neurosci Lett 463(3):176-181
62. Hentze H, Soong PL, Wang ST, Phillips BW, Putti TC, Dunn NR (2009) Teratoma formation by human embryonic stem cells: evaluation of essential parameters for future safety studies. Stem Cell Res 2(3):198-210. doi:10.1016/j.scr.2009.02.002
63. Hernigou P, Poignard A, Beaujean F, Rouard H (2005) Percutaneous autologous bone-marrow grafting for nonunions. Influence of the number and concentration of progenitor cells. J Bone Joint Surg Am 87(7):1430-1437 (Pubitemid 40917741)
64. Hinoi E, Bialek P, Chen YT et al (2006) Runx2 inhibits chondrocyte proliferation and hypertrophy through its expression in the perichondrium. Genes Dev 20(21):2937-2942. doi:10.1101/gad.1482906 (Pubitemid 44771727)
65. Houlihan DD, Mabuchi Y, Morikawa S et al (2012) Isolation of mouse mesenchymal stem cells on the basis of expression of Sca-1 and PDGFR-α. Nat Protoc 7(12):2103-2111
66. Huang W, Yang S, Shao J, Li YP (2007) Signaling and transcriptional regulation in osteoblast commitment and differentiation. Front Biosci 12:3068-3092
67. Huang J, Zhang Z, Guo J et al (2010) Genetic modification of mesenchymal stem cells overexpressing CR1 increases cell viability, migration, engraftment, and capillary density in the injured myocardium. Circ Res 106(11):1753-1762
68. Inanc B, Elcin AE, Elcin YM (2007) Effect of osteogenic induction on the in vitro differentiation of human embryonic stem cells cocultured with periodontal ligament fibroblasts. Artif Organs 31(11):792-800 (Pubitemid 350131991)
69. Jang H, Kim EJ, Park JK et al (2014) SMILE inhibits BMP-2-induced expression of osteocalcin by suppressing the activity of the RUNX2 transcription factor in MC3T3E1 cells. Bone. doi:10.1016/j.bone.2013.12.028
70. Jeevanantham V, Butler M, Saad A, Abdel-Latif A, Zuba-Surma EK, Dawn B (2012) Adult bone marrow cell therapy improves survival and induces long-term improvement in cardiac parameters: a systematic review and meta-analysis. Circulation 126(5):551-568. doi:10.1161/CIRCULATIONAHA.111.086074
71. Ji JF, He BP, Dheen ST, Tay SS (2004) Interactions of chemokines and chemokine receptors mediate the migration of mesenchymal stem cells to the impaired site in the brain after hypoglossal nerve injury. Stem Cells 22(3):415-427 (Pubitemid 38736625)
72. Jia J, Tian Q, Ling S, Liu Y, Yang S, Shao Z (2013) miR-145 suppresses osteogenic differentiation by targeting Sp7. FEBS Lett 587(18):3027-3031. doi:10.1016/j.febslet.2013.07.030
73. Karp JM, Leng Teo GS (2009) Mesenchymal stem cell homing: the devil is in the details. Cell Stem Cell 4(3):206-216
74. Karp JM, Ferreira LS, Khademhosseini A, Kwon AH, Yeh J, Langer RS (2006) Cultivation of human embryonic stem cells without the embryoid body step enhances osteogenesis in vitro. Stem Cells 24(4):835-843 (Pubitemid 44464716)
75. Kassem M, Marie PJ (2011) Senescence-associated intrinsic mechanisms of osteoblast dysfunctions. Aging Cell 10(2):191-197
76. Kassem M, Mosekilde L, Eriksen EF (1993) 1,25-dihydroxyvitamin D3 potentiates fluoride-stimulated collagen type I production in cultures of human bone marrow stromal osteoblast-like cells. J Bone Miner Res 8(12):1453-1458 (Pubitemid 23342682)
77. Kawai M, Green CB, Lecka-Czernik B et al (2010) A circadian-regulated gene, Nocturnin, promotes adipogenesis by stimulating PPAR-gamma nuclear translocation. Proc Natl Acad Sci USA 107(23):10508-10513. doi:10.1073/pnas. 1000788107
78. Kawate K, Yajima H, Ohgushi H et al (2006) Tissue-engineered approach for the treatment of steroid-induced osteonecrosis of the femoral head: transplantation of autologous mesenchymal stem cells cultured with beta-tricalcium phosphate ceramics and free vascularized fibula. Artif Organs 30(12):960-962 (Pubitemid 44915585)
79. Kebriaei P, Isola L, Bahceci E et al (2009) Adult human mesenchymal stem cells added to corticosteroid therapy for the treatment of acute graft-versus-host disease. Biol Blood Marrow Transpl 15(7):804-811
80. Kermani AJ, Fathi F, Mowla SJ (2008) Characterization and genetic manipulation of human umbilical cord vein mesenchymal stem cells: potential application in cell-based gene therapy. Rejuvenation Res 11(2):379-386. doi:10.1089/rej.2008.0674 (Pubitemid 351601180)
81. Kim HE, Bae E, Jeong DY et al (2013) Lipin1 regulates PPARgamma transcriptional activity. Biochem J 453(1):49-60. doi:10.1042/BJ20121598
82. Kitoh H, Kitakoji T, Tsuchiya H et al (2004) Transplantation of marrow-derived mesenchymal stem cells and platelet-rich plasma during distraction osteogenesis-a preliminary result of three cases. Bone 35(4):892-898. doi:10.1016/j.bone.2004.06.013 (Pubitemid 39349220)
83. Klinge PM, Harmening K, Miller MC et al (2011) Encapsulated native and glucagon-like peptide-1 transfected human mesenchymal stem cells in a transgenic mouse model of Alzheimer's disease. Neurosci Lett 497(1):6-10
84. Koga T, Matsui Y, Asagiri M et al (2005) NFAT and Osterix cooperatively regulate bone formation. Nat Med 11(8):880-885. doi:10.1038/nm1270 (Pubitemid 41161121)
85. Koromila T, Baniwal SK, Song YS, Martin A, Xiong J, Frenkel B (2014) Glucocorticoids antagonize RUNX2 during osteoblast differentiation in cultures of ST2 pluripotent mesenchymal cells. J Cell Biochem 115(1):27-33. doi:10.1002/jcb.24646
86. Kumar S, Wan C, Ramaswamy G, Clemens TL, Ponnazhagan S (2010) Mesenchymal stem cells expressing osteogenic and angiogenic factors synergistically enhance bone formation in a mouse model of segmental bone defect. Mol Ther 18(5):1026-1034
87. Kuznetsov SA, Krebsbach PH, Satomura K et al (1997) Single-colony derived strains of human marrow stromal fibroblasts form bone after transplantation in vivo. J Bone Miner Res Off J Am Soc Bone Miner Res 12(9):1335-1347 (Pubitemid 27375376)
88. Lange C, Brunswig-Spickenheier B, Cappallo-Obermann H et al (2011) Radiation rescue: mesenchymal stromal cells protect from lethal irradiation. PLoS One 6(1):e14486
89. Larsen KH, Frederiksen CM, Burns JS, Abdallah BM, Kassem M (2010) Identifying a molecular phenotype for bone marrow stromal cells with in vivo bone-forming capacity. J Bone Miner Res 25(4):796-808. doi:10.1359/jbmr.091018
90. Lawson KA, Teteak CJ, Gao J et al (2013) ESET histone methyltransferase regulates osteoblastic differentiation of mesenchymal stem cells during postnatal bone development. FEBS Lett 587(24):3961-3967. doi:10.1016/j.febslet. 2013.10.028
91. Lazarenko OP, Rzonca SO, Hogue WR, Swain FL, Suva LJ, Lecka-Czernik B (2007) Rosiglitazone induces decreases in bone mass and strength that are reminiscent of aged bone. Endocrinology 148(6):2669-2680. doi:10.1210/en.2006- 1587 (Pubitemid 46984815)
92. Le Blanc K, Ringden O (2007) Immunomodulation by mesenchymal stem cells and clinical experience. J Intern Med 262(5):509-525 (Pubitemid 47620502)
93. Le Blanc K, Gotherstrom C, Ringden O et al (2005) Fetal mesenchymal stem-cell engraftment in bone after in utero transplantation in a patient with severe osteogenesis imperfecta. Transplantation 79(11):1607-1614 (Pubitemid 40847594)
94. Le BK, Frassoni F, Ball L et al (2008) Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 371(9624):1579-1586 (Pubitemid 351626841)
95. Lee YH, Kim SH, Lee YJ et al (2013) Transcription factor Snail is a novel regulator of adipocyte differentiation via inhibiting the expression of peroxisome proliferator-activated receptor gamma. Cell Mol Life Sci 70(20):3959-3971. doi:10.1007/s00018-013-1363-8
96. Lefebvre V, Li P, de Crombrugghe B (1998) A new long form of Sox5 (L-Sox5), Sox6 and Sox9 are coexpressed in chondrogenesis and cooperatively activate the type II collagen gene. EMBO J 17(19):5718-5733. doi:10.1093/emboj/17.19.5718 (Pubitemid 28445983)
97. Lepperdinger G, Brunauer R, Jamnig A, Laschober G, Kassem M (2008) Controversial issue: is it safe to employ mesenchymal stem cells in cell-based therapies? Exp Gerontol 43(11):1018-1023
98. Leung VY, Gao B, Leung KK et al (2011) SOX9 governs differentiation stage-specific gene expression in growth plate chondrocytes via direct concomitant transactivation and repression. PLoS Genet 7(11):e1002356. doi:10.1371/journal.pgen.1002356
99. Levy O, Zhao W, Mortensen LJ et al (2013) mRNA-engineered mesenchymal stem cells for targeted delivery of inter-leukin-10 to sites of inflammation. Blood. doi:10.1182/ blood-2013-04-495119
100. Li W, Ma N, Ong L et al (2007) Bcl-2 engineered MSCs inhibited apoptosis and improved heart function. Stem Cells 25(8):2118-2127 (Pubitemid 47258191)
101. Li H, Jeong HM, Choi YH et al (2013a) Glycogen synthase kinase 3 alpha phosphorylates and regulates the osteogenic activity of Osterix. Biochem Biophys Res Commun 434(3):653-658. doi:10.1016/j.bbrc.2013.03.137
102. Li J, Zhang N, Huang X et al (2013b) Dexamethasone shifts bone marrow stromal cells from osteoblasts to adipocytes by C/EBPalpha promoter methylation. Cell Death Dis 4:e832. doi: 10.1038/cddis.2013.348
103. Li E, Zhang J, Yuan T, Ma B (2014) miR-143 suppresses osteogenic differentiation by targeting Osterix. Mol Cell Biochem. doi:10.1007/s11010-013- 1957-3
104. Lian Q, Lye E, Suan Yeo K et al (2007) Derivation of clinically compliant MSCs from CD105 +, CD24 - differentiated human ESCs. Stem Cells 25(2):425-436 (Pubitemid 46232798)
105. Lian Q, Zhang Y, Zhang J et al (2010) Functional mesenchymal stem cells derived from human induced pluripotent stem cells attenuate limb ischemia in mice. Circulation 121(9):1113-1123. doi:1 0.1161/CIRCULATIONAHA.109.898312
106. Liang J, Zhang H, Wang D et al (2012) Allogeneic mesenchymal stem cell transplantation in seven patients with refractory inflammatory bowel disease. Gut 61(3):468-469. doi:10.1136/gutjnl-2011-300083
107. Liao L, Yang X, Su X et al (2013) Redundant miR-3077-5p and miR-705 mediate the shift of mesenchymal stem cell lineage commitment to adipocyte in osteoporosis bone marrow. Cell Death Dis 4:e600. doi:10.1038/cddis.2013.130
108. Lin FT, Lane MD (1992) Antisense CAAT/enhancer-binding protein RNA suppresses coordinate gene expression and triglyceride accumulation during differentiation of 3T3-L1 preadipocytes. Genes Dev 6(4):533-544
109. Liu Y, Goldberg AJ, Dennis JE, Gronowicz GA, Kuhn LT (2012) One-Step derivation of mesenchymal stem cell (MSC)-like cells from human pluripotent stem cells on a fibrillar collagen coating. PLoS One 7(3):e33225. doi:10.1371/journal.pone.0033225
110. Mabuchi Y, Houlihan DD, Akazawa C, Okano H, Matsuzaki Y (2013) Prospective isolation of murine and human bone marrow mesenchymal stem cells based on surface markers. Stem Cells Int 2013:507301. doi:10.1155/2013/507301
111. Mahmood A, Harkness L, Schroder HD, Abdallah BM, Kassem M (2010) Enhanced differentiation of human embryonic stem cells to mesenchymal progenitors by inhibition of TGF-beta/activin/nodal signaling using SB-431542. J Bone Miner Res 25(6):1216-1233. doi:10.1002/jbmr.34
112. Mahmood A, Harkness L, Abdallah BM et al (2012) Derivation of stromal (skeletal and mesenchymal) stem-like cells from human embryonic stem cells. Stem Cells Dev 21(17):3114-3124. doi:10.1089/scd.2012.0035
113. Mangi AA, Noiseux N, Kong D et al (2003) Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nat Med 9(9):1195-1201 (Pubitemid 37173705)
114. Marie PJ (2008) Transcription factors controlling osteoblastogenesis. Arch Biochem Biophys 473(2):98-105. doi:10.1016/j.abb.2008.02.030
115. Martinez-Sanchez A, Dudek KA, Murphy CL (2012) Regulation of human chondrocyte function through direct inhibition of cartilage master regulator SOX9 by microRNA-145 (miRNA-145). J Biol Chem 287(2):916-924. doi:10.1074/jbc.M111.302430
116. Matsumoto Y, Ivasaki H, Suda T (2011) Maintenance of adult stem cells: role of the stem cell niche. In: Phinney DG (ed) Adult stem cells: biology and methods of analysis. Stem cell biology and regenerative medicine. Springer, Berlin, pp 35-55
117. Mirotsou M, Jayawardena TM, Schmeckpeper J, Gnecchi M, Dzau VJ (2011) Paracrine mechanisms of stem cell reparative and regenerative actions in the heart. J Mol Cell Cardiol 50(2):280-289. doi:10.1016/j.yjmcc.2010.08.005
118. Miura K, Okada Y, Aoi T, et al (2009) Variation in the safety of induced pluripotent stem cell lines. Nat Biotech 27(8):743-745 http://www.nature.com/ nbt/journal/v27/n8/suppinfo/nbt.1554-S1.html
119. Mohle R, Bautz F, Rafii S, Moore MA, Brugger W, Kanz L (1998) The chemokine receptor CXCR-4 is expressed on CD34 + hematopoietic progenitors and leukemic cells and mediates transendothelial migration induced by stromal cell-derived factor-1. Blood 91(12):4523-4530
120. Nakashima K, Zhou X, Kunkel G et al (2002) The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 108(1):17-29 (Pubitemid 34137009)
121. Nauta AJ, Fibbe WE (2007) Immunomodulatory properties of mesenchymal stromal cells. Blood 110(10):3499-3506. doi:10.1182/blood-2007-02-069716 (Pubitemid 350159613)
122. Nejadnik H, Hui JH, Feng Choong EP, Tai BC, Lee EH (2010) Autologous bone marrow-derived mesenchymal stem cells versus autologous chondrocyte implantation: an observational cohort study. Am J Sports Med 38(6):1110-1116. doi:10.1177/0363546509359067
123. Nishio Y, Dong Y, Paris M, O'Keefe RJ, Schwarz EM, Drissi H (2006) Runx2-mediated regulation of the zinc finger Osterix/Sp7 gene. Gene 372:62-70. doi:10.1016/j.gene.2005.12.022
124. Noiseux N, Gnecchi M, Lopez-Ilasaca M et al (2006) Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation. Mol Ther J Am Soc Gene Ther 14(6):840-850. doi:10.1016/j.ymthe.2006.05.016 (Pubitemid 44752717)
125. Nouspikel T (2013) Genetic instability in human embryonic stem cells: prospects and caveats. Future Oncol 9(6):867-877. doi:10.2217/fon.13.22
126. Nuttall ME, Shah F, Singh V, Thomas-Porch C, Frazier T, Gimble JM (2014) Adipocytes and the regulation of bone remodeling: a balancing act. Calcif Tissue Int 94(1):78-87. doi:10.1007/s00223-013-9807-6
127. Oh CD, Maity SN, Lu JF et al (2010) Identification of SOX9 interaction sites in the genome of chondrocytes. PLoS One 5(4):e10113. doi:10.1371/journal. pone.0010113
128. Olivier E, Bouhassira E (2011) Differentiation of human embryonic stem cells into mesenchymal stem cells by the raclure method. In: Nieden NI (ed) Embryonic stem cell therapy for Osteodegenerative diseases. Methods in molecular biology, vol 690. Humana, Clifton, pp 183-193
129. Orbay H, Tobita M, Mizuno H (2012) Mesenchymal stem cells isolated from adipose and other tissues: basic biological properties and clinical applications. Stem cells Int 461718. doi: 10.1155/2012/461718
130. Orozco L, Munar A, Soler R et al (2013) Treatment of knee osteoarthritis with autologous mesenchymal stem cells: a pilot study. Transplantation 95(12):1535-1541. doi:10.1097/TP.0b013e318291a2da
131. Ortuno MJ, Ruiz-Gaspa S, Rodriguez-Carballo E et al (2010) p38 regulates expression of osteoblast-specific genes by phosphorylation of osterix. J Biol Chem 285(42):31985-31994. doi:10.1074/jbc.M110.123612
132. Pal P, Lochab S, Kanaujiya JK et al (2013) E3 ubiquitin ligase E6AP negatively regulates adipogenesis by downregulating proadipogenic factor C/EBPalpha. PLoS One 8(6):e65330. doi:10.1371/journal.pone.0065330
133. Pan S, Yang X, Jia Y, Li R, Zhao R (2013) Microvesicle-shuttled miR-130b reduces fat deposition in recipient primary cultured porcine adipocytes by inhibiting PPAR-gamma expression. J Cell Physiol. doi:10.1002/jcp.24486
134. Park BO, Ahrends R, Teruel MN (2012) Consecutive positive feedback loops create a bistable switch that controls pread-ipocyte-to-adipocyte conversion. Cell Rep 2(4):976-990. doi:10.1016/j.celrep.2012.08.038
135. Paul G, Ozen I, Christophersen NS et al (2012) The adult human brain harbors multipotent perivascular mesenchymal stem cells. PLoS One 7(4):e35577. doi:10.1371/journal.pone.0035577
136. Peng Y, Shi K, Wang L et al (2013) Characterization of Osterix protein stability and physiological role in osteoblast differentiation. PLoS One 8(2):e56451. doi:10.1371/journal.pone.0056451
137. Perez-Ilzarbe M, Agbulut O, Pelacho B et al (2008) Characterization of the paracrine effects of human skeletal myoblasts transplanted in infarcted myocardium. Eur J Heart Fail 10(11):1065-1072. doi:10.1016/j.ejheart.2008.08.002
138. Porada CD, Almeida-Porada G (2010) Mesenchymal stem cells as therapeutics and vehicles for gene and drug delivery. Adv Drug Deliv Rev 62(12):1156-1166. doi:10.1016/j.addr.2010.08.010
139. Pratap J, Galindo M, Zaidi SK et al (2003) Cell growth regulatory role of Runx2 during proliferative expansion of preosteoblasts. Cancer Res 63(17):5357-5362 (Pubitemid 37139851)
140. Quesenberry PJ, Becker PS (1998) Stem cell homing: rolling, crawling, and nesting. Proc Natl Acad Sci USA 95(26):15155-15157
141. Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM, Morrison SJ (2008) Efficient tumour formation by single human melanoma cells. Nature 456(7222):593-598
142. Ringden O, Uzunel M, Rasmusson I et al (2006) Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation 81(10):1390-1397 (Pubitemid 43847148)
143. Sacchetti B, Funari A, Michienzi S et al (2007) Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131(2):324-336. doi:10.1016/j.cell.2007.08.025 (Pubitemid 47592917)
144. Samuelsson L, Stromberg K, Vikman K, Bjursell G, Enerback S (1991) The CAAT/enhancer binding protein and its role in adipocyte differentiation: evidence for direct involvement in terminal adipocyte development. EMBO J 10(12):3787-3793 (Pubitemid 21905407)
145. Sarkar D, Vemula PK, Zhao W, Gupta A, Karnik R, Karp JM (2010) Engineered mesenchymal stem cells with self-assembled vesicles for systemic cell targeting. Biomaterials 31(19):5266-5274. doi:10.1016/j.biomaterials.2010.03.006
146. Schaap-Oziemlak AM, Raymakers RA, Bergevoet SM et al (2010) MicroRNA hsa-miR-135b regulates mineralization in osteogenic differentiation of human unrestricted somatic stem cells. Stem Cells Dev 19(6):877-885. doi:10.1089/scd.2009.0112
147. Schrepfer S, Deuse T, Reichenspurner H, Fischbein MP, Robbins RC, Pelletier MP (2007) Stem cell transplantation: the lung barrier. Transpl Proc 39(2):573-576. doi:10.1016/j.transproceed.2006.12.019 (Pubitemid 46386222)
148. Schriebl K, Satianegara G, Hwang A et al (2012) Selective removal of undifferentiated human embryonic stem cells using magnetic activated cell sorting followed by a cytotoxic antibody. Tissue Eng Part A 18(9-10):899-909
149. Schuldiner M, Yanuka O, Itskovitz-Eldor J, Melton DA, Benvenisty N (2000) Effects of eight growth factors on the differentiation of cells derived from human embryonic stem cells. Proc Natl Acad Sci USA 97(21):11307-11312
150. Shi M, Li J, Liao L et al (2007) Regulation of CXCR4 expression in human mesenchymal stem cells by cytokine treatment: role in homing efficiency in NOD/SCID mice. Haematologica 92(7):897-904 (Pubitemid 350144236)
151. Shi K, Lu J, Zhao Y et al (2013) MicroRNA-214 suppresses osteogenic differentiation of C2C12 myoblast cells by targeting Osterix. Bone 55(2):487-494. doi:10.1016/j.bone.2013.04.002
152. Shiojima I, Walsh K (2006) Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway. Genes Dev 20(24):3347-3365. doi:10.1101/gad.1492806 (Pubitemid 44969154)
153. Shujia J, Haider HK, Idris NM, Lu G, Ashraf M (2008) Stable therapeutic effects of mesenchymal stem cell-based multiple gene delivery for cardiac repair. Cardiovasc Res 77(3):525-533 (Pubitemid 351197668)
154. Simonsen JL, Rosada C, Serakinci N et al (2002) Telomerase expression extends the proliferative life-span and maintains the osteogenic potential of human bone marrow stromal cells. Nat Biotechnol 20(6):592-596 (Pubitemid 34595153)
155. Sinha KM, Zhou X (2013) Genetic and molecular control of osterix in skeletal formation. J Cell Biochem 114(5):975-984. doi:10.1002/jcb.24439
156. Sinha KM, Yasuda H, Zhou X, Decrombrugghe B (2013) Osterix and NO66 histone demethylase control the chromatin architecture of Osterix target genes during osteoblast differentiation. J Bone Miner Res Off J Am Soc Bone Miner Res. doi:10.1002/jbmr.2103
157. Sordi V, Malosio ML, Marchesi F et al (2005) Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets. Blood 106(2):419-427 (Pubitemid 40981232)
158. Sottile V, Thomson A, McWhir J (2003) In Vitro Osteogenic Differentiation of Human ES Cells. Cloning Stem Cells 5(2):149-155 (Pubitemid 36877165)
159. Stenderup K, Justesen J, Clausen C, Kassem M (2003) Aging is associated with decreased maximal life span and accelerated senescence of bone marrow stromal cells. Bone 33(6):919-926. doi:10.1016/j.bone.2003.07.005 (Pubitemid 37543568)
160. Takada I, Kouzmenko AP, Kato S (2009a) Molecular switching of osteoblastogenesis versus adipogenesis: implications for targeted therapies. Expert Opin Ther Targets 13(5):593-603. doi:10.1517/14728220902915310
161. Takada I, Kouzmenko AP, Kato S (2009b) Wnt and PPARgamma signaling in osteoblastogenesis and adipogenesis. Nat Rev Rheumatol 5(8):442-447. doi:10.1038/nrrheum.2009.137
162. Tang QQ, Lane MD (2000) Role of C/EBP homologous protein (CHOP-10) in the programmed activation of CAAT/enhancer-binding protein-beta during adipogenesis. Proc Natl Acad Sci USA 97(23):12446-12450. doi:10.1073/pnas. 220425597
163. Tang C, Weissman IL, Drukker M (2012) The safety of embryonic stem cell therapy relies on teratoma removal. Oncotarget 3(1):7-8. PMID 22294556
164. Tao Z, Chen B, Tan X et al (2011) Coexpression of VEGF and angi-opoietin-1 promotes angiogenesis and cardiomyocyte proliferation reduces apoptosis in porcine myocardial infarction (MI) heart. Proc Natl Acad Sci USA 108(5):2064-2069. doi:10.1073/pnas.1018925108
165. Tong Q, Dalgin G, Xu H, Ting CN, Leiden JM, Hotamisligil GS (2000) Function of GATA transcription factors in preadipocyteadipocyte transition. Science 290(5489):134-138
166. Tong Q, Tsai J, Tan G, Dalgin G, Hotamisligil GS (2005) Interaction between GATA and the C/EBP family of transcription factors is critical in GATA-mediated suppression of adipocyte differentiation. Mol Cell Biol 25(2):706-715. doi:10.1128/MCB.25.2.706-715.2005 (Pubitemid 40096591)
167. Tontonoz P, Hu E, Graves RA, Budavari AI, Spiegelman BM (1994) mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev 8(10):1224-1234
168. Tormin A, Li O, Brune JC et al (2011) CD146 expression on primary nonhematopoietic bone marrow stem cells is correlated with in situ localization. Blood 117(19):5067-5077. doi:10.1182/blood-2010-08-304287
169. Tornvig L, Mosekilde LI, Justesen J, Falk E, Kassem M (2001) Troglitazone treatment increases bone marrow adipose tissue volume but does not affect trabecular bone volume in mice. Calcif Tissue Int 69(1):46-50. doi:10.1007/s002230020018 (Pubitemid 32702265)
170. Tremoleda JL, Forsyth NR, Khan NS et al (2008) Bone Tissue Formation from Human Embryonic Stem Cells In Vivo. Cloning Stem Cells 10(1):119-132
171. Trivedi P, Hematti P (2008) Derivation and immunological characterization of mesenchymal stromal cells from human embryonic stem cells. Exp Hematol 36(3):350-359
172. Tu Q, Valverde P, Li S, Zhang J, Yang P, Chen J (2007) Osterix over-expression in mesenchymal stem cells stimulates healing of critical-sized defects in murine calvarial bone. Tissue Eng 13(10):2431-2440 (Pubitemid 47571707)
173. Ueta C, Iwamoto M, Kanatani N et al (2001) Skeletal malformations caused by overexpression of Cbfa1 or its dominant negative form in chondrocytes. J Cell Biol 153(1):87-100
174. Vimalraj S, Partridge NC, Selvamurugan N (2014) A positive role of microRNA-15b on regulation of osteoblast differentiation. J Cell Physiol. doi:10.1002/jcp.24557
175. Wakitani S, Nawata M, Tensho K, Okabe T, Machida H, Ohgushi H (2007) Repair of articular cartilage defects in the patellofemoral joint with autologous bone marrow mesenchymal cell transplantation: three case reports involving nine defects in five knees. J Tissue Eng Regen Med 1(1):74-79. doi:10.1002/term.8
176. Wang YH, Han Z-B; Song Y-P; Han ZC (2012) Safety of mesenchymal stem cells for clinical application. Stem Cells Int 2012(Article ID 652034):4. doi: 10.1155/2012/652034
177. Wang CY, Yang SF, Wang Z et al (2013) PCAF acetylates Runx2 and promotes osteoblast differentiation. J Bone Miner Metab 31(4):381-389. doi:10.1007/s00774-013-0428-y
178. Weng JY, Du X, Geng SX et al (2010) Mesenchymal stem cell as salvage treatment for refractory chronic GVHD. Bone Marrow Transpl 45(12):1732-1740. doi:10.1038/bmt.2010.195
179. Wu Y, Zhao RC (2012) The role of chemokines in mesenchymal stem cell homing to myocardium. Stem Cell Rev 8(1):243-250
180. Xiao G, Jiang D, Thomas P et al (2000) MAPK pathways activate and phosphorylate the osteoblast-specific transcription factor, Cbfa1. J Biol Chem 275(6):4453-4459 (Pubitemid 30094689)
181. Yamashita S, Miyaki S, Kato Y et al (2012) L-Sox5 and Sox6 proteins enhance chondrogenic miR-140 microRNA expression by strengthening dimeric Sox9 activity. J Biol Chem 287(26):22206-22215. doi:10.1074/jbc.M112.343194
182. Yang L, Cheng P, Chen C et al (2012a) miR-93/Sp7 function loop mediates osteoblast mineralization. J Bone Miner Res Off J Am Soc Bone Miner Res 27(7):1598-1606. doi:10.1002/jbmr.1621
183. Yang X, Balakrishnan I, Torok-Storb B, Pillai MM (2012b) Marrow stromal cell infusion rescues hematopoiesis in lethally irradiated mice despite rapid clearance after infusion. Adv Hematol 2012:142530
184. Yang D, Okamura H, Nakashima Y, Haneji T (2013) Histone demethylase Jmjd3 regulates osteoblast differentiation via transcription factors Runx2 and osterix. J Biol Chem 288(47):33530-33541. doi:10.1074/jbc.M113.497040
185. Zhang JF, Fu WM, He ML et al (2011a) MiR-637 maintains the balance between adipocytes and osteoblasts by directly targeting Osterix. Mol Biol Cell 22(21):3955-3961. doi:10.1091/mbc.E11-04-0356
186. Zhang JF, Fu WM, He ML et al (2011b) MiRNA-20a promotes osteogenic differentiation of human mesenchymal stem cells by co-regulating BMP signaling. RNA Biol 8(5):829-838. doi:10.4161/rna.8.5.16043
187. Zhao S, Wehner R, Bornhauser M, Wassmuth R, Bachmann M, Schmitz M (2010) Immunomodulatory properties of mesenchymal stromal cells and their therapeutic consequences for immune-mediated disorders. Stem Cells Dev 19(5):607-614. doi:10.1089/scd.2009.0345
188. Zhou M, Ma J, Chen S, Chen X, Yu X (2013) MicroRNA-17-92 cluster regulates osteoblast proliferation and differentiation. Endocrine. doi:10.1007/s12020-013-9986-y
189. Zimmet H, Porapakkham P, Sata Y et al (2012) Short- and long-term outcomes of intracoronary and endogenously mobilized bone marrow stem cells in the treatment of ST-segment elevation myocardial infarction: a meta-analysis of randomized control trials. Eur J Heart Fail 14(1):91-105. doi:10.1093/eurjhf/ hfr148