Cellular and Molecular Life Sciences

, Volume 75, Issue 19, pp 3507–3520 | Cite as

The mesenchymoangioblast, mesodermal precursor for mesenchymal and endothelial cells

  • Igor I. SlukvinEmail author
  • Akhilesh Kumar


Mesenchymoangioblast (MB) is the earliest precursor for endothelial and mesenchymal cells originating from APLNR+PDGFRα+KDR+ mesoderm in human pluripotent stem cell cultures. MBs are identified based on their capacity to form FGF2-dependent compact spheroid colonies in a serum-free semisolid medium. MBs colonies are composed of PDGFRβ+CD271+EMCN+DLK1+CD73 primitive mesenchymal cells which are generated through endothelial/angioblastic intermediates (cores) formed during first 3–4 days of clonogenic cultures. MB-derived primitive mesenchymal cells have potential to differentiate into mesenchymal stromal/stem cells (MSCs), pericytes, and smooth muscle cells. In this review, we summarize the specification and developmental potential of MBs, emphasize features that distinguish MBs from other mesenchymal progenitors described in the literature and discuss the value of these findings for identifying molecular pathways leading to MSC and vasculogenic cell specification, and developing cellular therapies using MB-derived progeny.


Mesenchymoangioblasts Human pluripotent stem cells Embryonic stem cells Induced pluripotent stem cells Mesoderm development Mesenchymal stem cells Mesoangioblast Mesospheres Hemangioblasts Cardiovascular progenitors Pericytes Smooth muscles Embryonic mesenchyme 









Smooth muscle cells


Mesenchymal stem/stromal cells


Human pluripotent stem cells


Human embryonic stem cells


Human-induced pluripotent stem cells



We thank Matthew Raymond for editorial assistance. I.I.S. and A.K are supported by funds from the National Institute of Health (U01HL134655, U01HL099773 and P51 RR000167). I.I.S. is a founding shareholder and consultant for Cynata Therapeutics.


  1. 1.
    Vodyanik MA, Yu J, Zhang X, Tian S, Stewart R, Thomson JA, Slukvin II (2010) A mesoderm-derived precursor for mesenchymal stem and endothelial cells. Cell Stem Cell 7(6):718–729. PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Tam PP, Behringer RR (1997) Mouse gastrulation: the formation of a mammalian body plan. Mech Dev 68(1–2):3–25PubMedCrossRefGoogle Scholar
  3. 3.
    Lawson A, Schoenwolf GC (2001) Cell populations and morphogenetic movements underlying formation of the avian primitive streak and organizer. Genesis 29(4):188–195PubMedCrossRefGoogle Scholar
  4. 4.
    Sadler TW (2006) Langman’s medical embryology. Lippincott Williams and Wilkins, PhiladelphiaGoogle Scholar
  5. 5.
    Hay ED (2005) The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it. Dev Dyn 233(3):706–720. PubMedCrossRefGoogle Scholar
  6. 6.
    Noden DM (1978) The control of avian cephalic neural crest cytodifferentiation. I. Skeletal and connective tissues. Dev Biol 67(2):296–312PubMedCrossRefGoogle Scholar
  7. 7.
    Noden DM (1986) Origins and patterning of craniofacial mesenchymal tissues. J Craniofac Genet Dev Biol Suppl 2:15–31PubMedGoogle Scholar
  8. 8.
    Mayor R, Theveneau E (2013) The neural crest. Development 140(11):2247–2251. PubMedCrossRefGoogle Scholar
  9. 9.
    Majesky MW (2007) Developmental basis of vascular smooth muscle diversity. Arterioscler Thromb Vasc Biol 27(6):1248–1258. PubMedCrossRefGoogle Scholar
  10. 10.
    Takashima Y, Era T, Nakao K, Kondo S, Kasuga M, Smith AG, Nishikawa S (2007) Neuroepithelial cells supply an initial transient wave of MSC differentiation. Cell 129(7):1377–1388. PubMedCrossRefGoogle Scholar
  11. 11.
    Isern J, Garcia-Garcia A, Martin AM, Arranz L, Martin-Perez D, Torroja C, Sanchez-Cabo F, Mendez-Ferrer S (2014) The neural crest is a source of mesenchymal stem cells with specialized hematopoietic stem cell niche function. Elife 3:e03696. PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Miller FD (2007) Riding the waves: neural and nonneural origins for mesenchymal stem cells. Cell Stem Cell 1(2):129–130. PubMedCrossRefGoogle Scholar
  13. 13.
    Morikawa S, Mabuchi Y, Niibe K, Suzuki S, Nagoshi N, Sunabori T, Shimmura S, Nagai Y, Nakagawa T, Okano H, Matsuzaki Y (2009) Development of mesenchymal stem cells partially originate from the neural crest. Biochem Biophys Res Commun 379(4):1114–1119. PubMedCrossRefGoogle Scholar
  14. 14.
    Rossant J, Tam PPL (2017) New insights into early human development: lessons for stem cell derivation and differentiation. Cell Stem Cell 20(1):18–28. PubMedCrossRefGoogle Scholar
  15. 15.
    Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM (1998) Embryonic stem cell lines derived from human blastocysts. Science 282(5391):1145–1147PubMedCrossRefGoogle Scholar
  16. 16.
    Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5):861–872. PubMedCrossRefGoogle Scholar
  17. 17.
    Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318(5858):1917–1920. PubMedCrossRefGoogle Scholar
  18. 18.
    Patsch C, Challet-Meylan L, Thoma EC, Urich E, Heckel T, O’Sullivan JF, Grainger SJ, Kapp FG, Sun L, Christensen K, Xia Y, Florido MH, He W, Pan W, Prummer M, Warren CR, Jakob-Roetne R, Certa U, Jagasia R, Freskgard PO, Adatto I, Kling D, Huang P, Zon LI, Chaikof EL, Gerszten RE, Graf M, Iacone R, Cowan CA (2015) Generation of vascular endothelial and smooth muscle cells from human pluripotent stem cells. Nat Cell Biol 17(8):994–1003. PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Orlova VV, Drabsch Y, Freund C, Petrus-Reurer S, van den Hil FE, Muenthaisong S, Dijke PT, Mummery CL (2014) Functionality of endothelial cells and pericytes from human pluripotent stem cells demonstrated in cultured vascular plexus and zebrafish xenografts. Arterioscler Thromb Vasc Biol 34(1):177–186. PubMedCrossRefGoogle Scholar
  20. 20.
    Dar A, Domev H, Ben-Yosef O, Tzukerman M, Zeevi-Levin N, Novak A, Germanguz I, Amit M, Itskovitz-Eldor J (2012) Multipotent vasculogenic pericytes from human pluripotent stem cells promote recovery of murine ischemic limb. Circulation 125(1):87–99. PubMedCrossRefGoogle Scholar
  21. 21.
    Cheung C, Bernardo AS, Trotter MW, Pedersen RA, Sinha S (2012) Generation of human vascular smooth muscle subtypes provides insight into embryological origin-dependent disease susceptibility. Nat Biotechnol 30(2):165–173. PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Uenishi G, Theisen D, Lee JH, Kumar A, Raymond M, Vodyanik M, Swanson S, Stewart R, Thomson J, Slukvin I (2014) Tenascin C promotes hematoendothelial development and T lymphoid commitment from human pluripotent stem cells in chemically defined conditions. Stem Cell Rep 3(6):1073–1084. CrossRefGoogle Scholar
  23. 23.
    Flamme I, Breier G, Risau W (1995) Vascular endothelial growth factor (VEGF) and VEGF receptor 2 (flk-1) are expressed during vasculogenesis and vascular differentiation in the quail embryo. Dev Biol 169(2):699–712. PubMedCrossRefGoogle Scholar
  24. 24.
    Risau W, Flamme I (1995) Vasculogenesis. Annu Rev Cell Dev Biol 11:73–91. PubMedCrossRefGoogle Scholar
  25. 25.
    Kumar A, D’Souza SS, Moskvin OV, Toh H, Wang B, Zhang J, Swanson S, Guo LW, Thomson JA, Slukvin II (2017) Specification and diversification of pericytes and smooth muscle cells from mesenchymoangioblasts. Cell Rep 19(9):1902–1916. PubMedCrossRefGoogle Scholar
  26. 26.
    Hafner AL, Contet J, Ravaud C, Yao X, Villageois P, Suknuntha K, Annab K, Peraldi P, Binetruy B, Slukvin II, Ladoux A, Dani C (2016) Brown-like adipose progenitors derived from human induced pluripotent stem cells: Identification of critical pathways governing their adipogenic capacity. Sci Rep 6:32490. PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Armulik A, Genove G, Betsholtz C (2011) Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell 21(2):193–215. PubMedCrossRefGoogle Scholar
  28. 28.
    Shen EM, McCloskey KE (2017) Development of mural cells: from in vivo understanding to in vitro recapitulation. Stem Cells Dev 26(14):1020–1041. PubMedCrossRefGoogle Scholar
  29. 29.
    D’Aniello C, Lonardo E, Iaconis S, Guardiola O, Liguoro AM, Liguori GL, Autiero M, Carmeliet P, Minchiotti G (2009) G protein-coupled receptor APJ and its ligand apelin act downstream of Cripto to specify embryonic stem cells toward the cardiac lineage through extracellular signal-regulated kinase/p70S6 kinase signaling pathway. Circ Res 105(3):231–238. PubMedCrossRefGoogle Scholar
  30. 30.
    Devic E, Paquereau L, Vernier P, Knibiehler B, Audigier Y (1996) Expression of a new G protein-coupled receptor X-msr is associated with an endothelial lineage in Xenopus laevis. Mech Dev 59(2):129–140PubMedCrossRefGoogle Scholar
  31. 31.
    Zeng XX, Wilm TP, Sepich DS, Solnica-Krezel L (2007) Apelin and its receptor control heart field formation during zebrafish gastrulation. Dev Cell 12(3):391–402. PubMedCrossRefGoogle Scholar
  32. 32.
    Orr-Urtreger A, Bedford MT, Do MS, Eisenbach L, Lonai P (1992) Developmental expression of the alpha receptor for platelet-derived growth factor, which is deleted in the embryonic lethal Patch mutation. Development 115(1):289–303PubMedGoogle Scholar
  33. 33.
    Sakurai H, Era T, Jakt LM, Okada M, Nakai S, Nishikawa S (2006) In vitro modeling of paraxial and lateral mesoderm differentiation reveals early reversibility. Stem Cells 24(3):575–586. PubMedCrossRefGoogle Scholar
  34. 34.
    Yamaguchi TP, Dumont DJ, Conlon RA, Breitman ML, Rossant J (1993) flk-1, an flt-related receptor tyrosine kinase is an early marker for endothelial cell precursors. Development 118(2):489–498PubMedGoogle Scholar
  35. 35.
    Choi KD, Vodyanik MA, Togarrati PP, Suknuntha K, Kumar A, Samarjeet F, Probasco MD, Tian S, Stewart R, Thomson JA, Slukvin II (2012) Identification of the hemogenic endothelial progenitor and its direct precursor in human pluripotent stem cell differentiation cultures. Cell Rep 2(3):553–567. PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Slukvin II (2013) Deciphering the hierarchy of angiohematopoietic progenitors from human pluripotent stem cells. Cell Cycle 12(5):720–727. PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Flamme I, Frolich T, Risau W (1997) Molecular mechanisms of vasculogenesis and embryonic angiogenesis. J Cell Physiol 173(2):206–210.<206:AID-JCP22>3.0.CO;2-CGoogle Scholar
  38. 38.
    Greenbaum A, Hsu YM, Day RB, Schuettpelz LG, Christopher MJ, Borgerding JN, Nagasawa T, Link DC (2013) CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature 495(7440):227–230. PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Khan JA, Mendelson A, Kunisaki Y, Birbrair A, Kou Y, Arnal-Estape A, Pinho S, Ciero P, Nakahara F, Ma’ayan A, Bergman A, Merad M, Frenette PS (2015) Fetal liver hematopoietic stem cell niches associate with portal vessels. Science. PubMedCentralCrossRefPubMedGoogle Scholar
  40. 40.
    Crisan M, Yap S, Casteilla L, Chen CW, Corselli M, Park TS, Andriolo G, Sun B, Zheng B, Zhang L, Norotte C, Teng PN, Traas J, Schugar R, Deasy BM, Badylak S, Buhring HJ, Giacobino JP, Lazzari L, Huard J, Peault B (2008) A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3(3):301–313. PubMedCrossRefGoogle Scholar
  41. 41.
    Minasi MG, Riminucci M, De Angelis L, Borello U, Berarducci B, Innocenzi A, Caprioli A, Sirabella D, Baiocchi M, De Maria R, Boratto R, Jaffredo T, Broccoli V, Bianco P, Cossu G (2002) The meso-angioblast: a multipotent, self-renewing cell that originates from the dorsal aorta and differentiates into most mesodermal tissues. Development 129(11):2773–2783PubMedGoogle Scholar
  42. 42.
    Tonlorenzi R, Dellavalle A, Schnapp E, Cossu G, Sampaolesi M (2007) Isolation and characterization of mesoangioblasts from mouse, dog, and human tissues. Curr Protoc Stem Cell Biol Chapter 2:Unit 2B 1. PubMedCrossRefGoogle Scholar
  43. 43.
    Dellavalle A, Sampaolesi M, Tonlorenzi R, Tagliafico E, Sacchetti B, Perani L, Innocenzi A, Galvez BG, Messina G, Morosetti R, Li S, Belicchi M, Peretti G, Chamberlain JS, Wright WE, Torrente Y, Ferrari S, Bianco P, Cossu G (2007) Pericytes of human skeletal muscle are myogenic precursors distinct from satellite cells. Nat Cell Biol 9(3):255–267. PubMedCrossRefGoogle Scholar
  44. 44.
    Loperfido M, Jarmin S, Dastidar S, Di Matteo M, Perini I, Moore M, Nair N, Samara-Kuko E, Athanasopoulos T, Tedesco FS, Dickson G, Sampaolesi M, VandenDriessche T, Chuah MK (2016) piggyBac transposons expressing full-length human dystrophin enable genetic correction of dystrophic mesoangioblasts. Nucleic Acids Res 44(2):744–760. PubMedCrossRefGoogle Scholar
  45. 45.
    Iyer PS, Mavoungou LO, Ronzoni F, Zemla J, Schmid-Siegert E, Antonini S, Neff LA, Dorchies OM, Jaconi M, Lekka M, Messina G, Mermod N (2018) Autologous cell therapy approach for duchenne muscular dystrophy using piggybac transposons and mesoangioblasts. Mol Ther 26(4):1093–1108. PubMedCrossRefGoogle Scholar
  46. 46.
    Tedesco FS, Gerli MF, Perani L, Benedetti S, Ungaro F, Cassano M, Antonini S, Tagliafico E, Artusi V, Longa E, Tonlorenzi R, Ragazzi M, Calderazzi G, Hoshiya H, Cappellari O, Mora M, Schoser B, Schneiderat P, Oshimura M, Bottinelli R, Sampaolesi M, Torrente Y, Broccoli V, Cossu G (2012) Transplantation of genetically corrected human iPSC-derived progenitors in mice with limb-girdle muscular dystrophy. Sci Transl Med 4(140):140ra189. CrossRefGoogle Scholar
  47. 47.
    Dekel I, Magal Y, Pearson-White S, Emerson CP, Shani M (1992) Conditional conversion of ES cells to skeletal muscle by an exogenous MyoD1 gene. New Biol 4(3):217–224PubMedGoogle Scholar
  48. 48.
    Rao L, Tang W, Wei Y, Bao L, Chen J, Chen H, He L, Lu P, Ren J, Wu L, Luan Z, Cui C, Xiao L (2012) Highly efficient derivation of skeletal myotubes from human embryonic stem cells. Stem Cell Rev 8(4):1109–1119. PubMedCrossRefGoogle Scholar
  49. 49.
    Davis RL, Weintraub H, Lassar AB (1987) Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 51(6):987–1000PubMedCrossRefGoogle Scholar
  50. 50.
    Tanaka A, Woltjen K, Miyake K, Hotta A, Ikeya M, Yamamoto T, Nishino T, Shoji E, Sehara-Fujisawa A, Manabe Y, Fujii N, Hanaoka K, Era T, Yamashita S, Isobe K, Kimura E, Sakurai H (2013) Efficient and reproducible myogenic differentiation from human iPS cells: prospects for modeling Miyoshi Myopathy in vitro. PLoS One 8(4):e61540. PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Bonfanti C, Rossi G, Tedesco FS, Giannotta M, Benedetti S, Tonlorenzi R, Antonini S, Marazzi G, Dejana E, Sassoon D, Cossu G, Messina G (2015) PW1/Peg3 expression regulates key properties that determine mesoangioblast stem cell competence. Nat Commun 6:6364. PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Huber TL, Kouskoff V, Fehling HJ, Palis J, Keller G (2004) Haemangioblast commitment is initiated in the primitive streak of the mouse embryo. Nature 432(7017):625–630. PubMedCrossRefGoogle Scholar
  53. 53.
    Kattman SJ, Huber TL, Keller GM (2006) Multipotent flk-1+ cardiovascular progenitor cells give rise to the cardiomyocyte, endothelial, and vascular smooth muscle lineages. Dev Cell 11(5):723–732. PubMedCrossRefGoogle Scholar
  54. 54.
    Yang L, Soonpaa MH, Adler ED, Roepke TK, Kattman SJ, Kennedy M, Henckaerts E, Bonham K, Abbott GW, Linden RM, Field LJ, Keller GM (2008) Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population. Nature 453(7194):524–528. PubMedCrossRefGoogle Scholar
  55. 55.
    Kennedy M, Firpo M, Choi K, Wall C, Robertson S, Kabrun N, Keller G (1997) A common precursor for primitive erythropoiesis and definitive haematopoiesis. Nature 386(6624):488–493. PubMedCrossRefGoogle Scholar
  56. 56.
    Choi K, Kennedy M, Kazarov A, Papadimitriou JC, Keller G (1998) A common precursor for hematopoietic and endothelial cells. Development 125(4):725–732PubMedGoogle Scholar
  57. 57.
    Lancrin C, Sroczynska P, Stephenson C, Allen T, Kouskoff V, Lacaud G (2009) The haemangioblast generates haematopoietic cells through a haemogenic endothelium stage. Nature 457(7231):892–895. PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Kimbrel EA, Kouris NA, Yavanian GJ, Chu J, Qin Y, Chan A, Singh RP, McCurdy D, Gordon L, Levinson RD, Lanza R (2014) Mesenchymal stem cell population derived from human pluripotent stem cells displays potent immunomodulatory and therapeutic properties. Stem Cells Dev 23(14):1611–1624. PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Gertow K, Hirst CE, Yu QC, Ng ES, Pereira LA, Davis RP, Stanley EG, Elefanty AG (2013) WNT3A promotes hematopoietic or mesenchymal differentiation from hESCs depending on the time of exposure. Stem Cell Rep 1(1):53–65. CrossRefGoogle Scholar
  60. 60.
    Faloon P, Arentson E, Kazarov A, Deng CX, Porcher C, Orkin S, Choi K (2000) Basic fibroblast growth factor positively regulates hematopoietic development. Development 127(9):1931–1941PubMedGoogle Scholar
  61. 61.
    Robertson SM, Kennedy M, Shannon JM, Keller G (2000) A transitional stage in the commitment of mesoderm to hematopoiesis requiring the transcription factor SCL/tal-1. Development 127(11):2447–2459PubMedGoogle Scholar
  62. 62.
    Kattman SJ, Witty AD, Gagliardi M, Dubois NC, Niapour M, Hotta A, Ellis J, Keller G (2011) Stage-specific optimization of activin/nodal and BMP signaling promotes cardiac differentiation of mouse and human pluripotent stem cell lines. Cell Stem Cell 8(2):228–240. PubMedCrossRefGoogle Scholar
  63. 63.
    Kennedy M, D’Souza SL, Lynch-Kattman M, Schwantz S, Keller G (2007) Development of the hemangioblast defines the onset of hematopoiesis in human ES cell differentiation cultures. Blood 109(7):2679–2687. PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Slukvin II, Vodyanik M (2011) Endothelial origin of mesenchymal stem cells. Cell Cycle 10(9):1370–1373PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Yamashita J, Itoh H, Hirashima M, Ogawa M, Nishikawa S, Yurugi T, Naito M, Nakao K (2000) Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors. Nature 408(6808):92–96. PubMedCrossRefGoogle Scholar
  66. 66.
    Evseenko D, Zhu Y, Schenke-Layland K, Kuo J, Latour B, Ge S, Scholes J, Dravid G, Li X, MacLellan WR, Crooks GM (2010) Mapping the first stages of mesoderm commitment during differentiation of human embryonic stem cells. Proc Natl Acad Sci USA 107(31):13742–13747. PubMedCrossRefGoogle Scholar
  67. 67.
    Chin CJ, Cooper AR, Lill GR, Evseenko D, Zhu Y, He CB, Casero D, Pellegrini M, Kohn DB, Crooks GM (2016) Genetic tagging during human mesoderm differentiation reveals tripotent lateral plate mesodermal progenitors. Stem Cells 34(5):1239–1250. PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Murray IR, West CC, Hardy WR, James AW, Park TS, Nguyen A, Tawonsawatruk T, Lazzari L, Soo C, Peault B (2014) Natural history of mesenchymal stem cells, from vessel walls to culture vessels. Cell Mol Life Sci 71(8):1353–1374. PubMedCrossRefGoogle Scholar
  69. 69.
    Murphy MB, Moncivais K, Caplan AI (2013) Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine. Exp Mol Med 45:e54. PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Sharma RR, Pollock K, Hubel A, McKenna D (2014) Mesenchymal stem or stromal cells: a review of clinical applications and manufacturing practices. Transfusion 54(5):1418–1437. PubMedCrossRefGoogle Scholar
  71. 71.
    Galleu A, Riffo-Vasquez Y, Trento C, Lomas C, Dolcetti L, Cheung TS, von Bonin M, Barbieri L, Halai K, Ward S, Weng L, Chakraverty R, Lombardi G, Watt FM, Orchard K, Marks DI, Apperley J, Bornhauser M, Walczak H, Bennett C, Dazzi F (2017) Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation. Sci Transl Med 9(416):eaam7828. PubMedCrossRefGoogle Scholar
  72. 72.
    Majka M, Sulkowski M, Badyra B, Musialek P (2017) Concise review: mesenchymal stem cells in cardiovascular regeneration: emerging research directions and clinical applications. Stem Cells Transl Med 6(10):1859–1867. PubMedCrossRefGoogle Scholar
  73. 73.
    Munneke JM, Spruit MJA, Cornelissen AS, van Hoeven V, Voermans C, Hazenberg MD (2016) The potential of mesenchymal stromal cells as treatment for severe steroid-refractory acute graft-versus-host disease: a critical review of the literature. Transplantation 100(11):2309–2314PubMedCrossRefGoogle Scholar
  74. 74.
    Mendicino M, Bailey AM, Wonnacott K, Puri RK, Bauer SR (2014) MSC-based product characterization for clinical trials: an FDA perspective. Cell Stem Cell 14(2):141–145. PubMedCrossRefGoogle Scholar
  75. 75.
    Viswanathan S, Keating A, Deans R, Hematti P, Prockop D, Stroncek DF, Stacey G, Weiss DJ, Mason C, Rao MS (2014) Soliciting strategies for developing cell-based reference materials to advance mesenchymal stromal cell research and clinical translation. Stem Cells Dev 23(11):1157–1167. PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Martin I, De Boer J, Sensebe L, Therapy MSCCotISfC (2016) A relativity concept in mesenchymal stromal cell manufacturing. Cytotherapy 18(5):613–620. PubMedCrossRefGoogle Scholar
  77. 77.
    Liu ST, de Castro LF, Jin P, Civini S, Ren JQ, Reems JA, Cancelas J, Nayak R, Shaw G, O’Brien T, McKenna DH, Armant M, Silberstein L, Gee AP, Hei DJ, Hematti P, Kuznetsov SA, Robey PG, Stroncek DF (2017) Manufacturing differences affect human bone marrow stromal cell characteristics and function: comparison of production methods and products from multiple centers. Sci Rep 7:46731PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Chin CJ, Li S, Corselli M, Casero D, Zhu Y, He CB, Hardy R, Peault B, Crooks GM (2018) Transcriptionally and functionally distinct mesenchymal subpopulations are generated from human pluripotent stem cells. Stem Cell Rep. CrossRefGoogle Scholar
  79. 79.
    Luzzani CD, Miriuka SG (2017) Pluripotent stem cells as a robust source of mesenchymal stem cells. Stem Cell Rev 13(1):68–78. PubMedCrossRefGoogle Scholar
  80. 80.
    Xu J, Gong T, Heng BC, Zhang CF (2017) A systematic review: differentiation of stem cells into functional pericytes. FASEB J 31(5):1775–1786. PubMedCrossRefGoogle Scholar
  81. 81.
    Maguire EM, Xiao Q, Xu Q (2017) Differentiation and application of induced pluripotent stem cell-derived vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 37(11):2026–2037. PubMedCrossRefGoogle Scholar
  82. 82.
    Neofytou E, O’Brien CG, Couture LA, Wu JC (2015) Hurdles to clinical translation of human induced pluripotent stem cells. J Clin Investig 125(7):2551–2557. PubMedCrossRefGoogle Scholar
  83. 83.
    Trounson A, DeWitt ND (2016) Pluripotent stem cells progressing to the clinic. Nat Rev Mol Cell Biol 17(3):194–200. PubMedCrossRefGoogle Scholar
  84. 84.
    Tapia A, Salgado MS, Martin MP, Lapuerta M, Rodriguez-Fernandez J, Rossi MJ, Cabanas B (2016) Molecular characterization of the gas-particle interface of soot sampled from a diesel engine using a titration method. Environ Sci Technol 50(6):2946–2955. PubMedCrossRefGoogle Scholar
  85. 85.
    Takahashi K, Yamanaka S (2016) A decade of transcription factor-mediated reprogramming to pluripotency. Nat Rev Mol Cell Biol 17(3):183–193. PubMedCrossRefGoogle Scholar
  86. 86.
    Abyzov A, Mariani J, Palejev D, Zhang Y, Haney MS, Tomasini L, Ferrandino AF, Rosenberg Belmaker LA, Szekely A, Wilson M, Kocabas A, Calixto NE, Grigorenko EL, Huttner A, Chawarska K, Weissman S, Urban AE, Gerstein M, Vaccarino FM (2012) Somatic copy number mosaicism in human skin revealed by induced pluripotent stem cells. Nature 492(7429):438–442. PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Cheng L, Hansen NF, Zhao L, Du Y, Zou C, Donovan FX, Chou BK, Zhou G, Li S, Dowey SN, Ye Z, Program NCS, Chandrasekharappa SC, Yang H, Mullikin JC, Liu PP (2012) Low incidence of DNA sequence variation in human induced pluripotent stem cells generated by nonintegrating plasmid expression. Cell Stem Cell 10(3):337–344. PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Young MA, Larson DE, Sun CW, George DR, Ding L, Miller CA, Lin L, Pawlik KM, Chen K, Fan X, Schmidt H, Kalicki-Veizer J, Cook LL, Swift GW, Demeter RT, Wendl MC, Sands MS, Mardis ER, Wilson RK, Townes TM, Ley TJ (2012) Background mutations in parental cells account for most of the genetic heterogeneity of induced pluripotent stem cells. Cell Stem Cell 10(5):570–582. PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Hussein SM, Batada NN, Vuoristo S, Ching RW, Autio R, Narva E, Ng S, Sourour M, Hamalainen R, Olsson C, Lundin K, Mikkola M, Trokovic R, Peitz M, Brustle O, Bazett-Jones DP, Alitalo K, Lahesmaa R, Nagy A, Otonkoski T (2011) Copy number variation and selection during reprogramming to pluripotency. Nature 471(7336):58–62. PubMedCrossRefGoogle Scholar
  90. 90.
    Gore A, Li Z, Fung HL, Young JE, Agarwal S, Antosiewicz-Bourget J, Canto I, Giorgetti A, Israel MA, Kiskinis E, Lee JH, Loh YH, Manos PD, Montserrat N, Panopoulos AD, Ruiz S, Wilbert ML, Yu J, Kirkness EF, Izpisua Belmonte JC, Rossi DJ, Thomson JA, Eggan K, Daley GQ, Goldstein LS, Zhang K (2011) Somatic coding mutations in human induced pluripotent stem cells. Nature 471(7336):63–67. PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Laurent LC, Ulitsky I, Slavin I, Tran H, Schork A, Morey R, Lynch C, Harness JV, Lee S, Barrero MJ, Ku S, Martynova M, Semechkin R, Galat V, Gottesfeld J, Izpisua Belmonte JC, Murry C, Keirstead HS, Park HS, Schmidt U, Laslett AL, Muller FJ, Nievergelt CM, Shamir R, Loring JF (2011) Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture. Cell Stem Cell 8(1):106–118. PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Varela C, Denis JA, Polentes J, Feyeux M, Aubert S, Champon B, Pietu G, Peschanski M, Lefort N (2012) Recurrent genomic instability of chromosome 1q in neural derivatives of human embryonic stem cells. J Clin Investig 122(2):569–574. PubMedCrossRefGoogle Scholar
  93. 93.
    Lei Y, Schaffer DV (2013) A fully defined and scalable 3D culture system for human pluripotent stem cell expansion and differentiation. Proc Natl Acad Sci USA 110(52):E5039–E5048. PubMedCrossRefGoogle Scholar
  94. 94.
    Baxter MA, Wynn RF, Jowitt SN, Wraith JE, Fairbairn LJ, Bellantuono I (2004) Study of telomere length reveals rapid aging of human marrow stromal cells following in vitro expansion. Stem Cells 22(5):675–682. PubMedCrossRefGoogle Scholar
  95. 95.
    Bonab MM, Alimoghaddam K, Talebian F, Ghaffari SH, Ghavamzadeh A, Nikbin B (2006) Aging of mesenchymal stem cell in vitro. BMC Cell Biol 7:14. PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Chen G, Gulbranson DR, Hou Z, Bolin JM, Ruotti V, Probasco MD, Smuga-Otto K, Howden SE, Diol NR, Propson NE, Wagner R, Lee GO, Antosiewicz-Bourget J, Teng JM, Thomson JA (2011) Chemically defined conditions for human iPSC derivation and culture. Nat Methods 8(5):424–429. PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Wang X, Kimbrel EA, Ijichi K, Paul D, Lazorchak AS, Chu J, Kouris NA, Yavanian GJ, Lu SJ, Pachter JS, Crocker SJ, Lanza R, Xu RH (2014) Human ESC-derived MSCs outperform bone marrow MSCs in the treatment of an EAE model of multiple sclerosis. Stem Cell Rep 3(1):115–130. CrossRefGoogle Scholar
  98. 98.
    Zhang Y, Liao S, Yang M, Liang X, Poon MW, Wong CY, Wang J, Zhou Z, Cheong SK, Lee CN, Tse HF, Lian Q (2012) Improved cell survival and paracrine capacity of human embryonic stem cell-derived mesenchymal stem cells promote therapeutic potential for pulmonary arterial hypertension. Cell Transpl 21(10):2225–2239. CrossRefGoogle Scholar
  99. 99.
    Hao Q, Zhu YG, Monsel A, Gennai S, Lee T, Xu F, Lee JW (2015) Study of bone marrow and embryonic stem cell-derived human mesenchymal stem cells for treatment of Escherichia coli endotoxin-induced acute lung injury in mice. Stem Cells Transl Med 4(7):832–840. PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Zhang Y, Liang X, Liao S, Wang W, Wang J, Li X, Ding Y, Liang Y, Gao F, Yang M, Fu Q, Xu A, Chai YH, He J, Tse HF, Lian Q (2015) Potent paracrine effects of human induced pluripotent stem cell-derived mesenchymal stem cells attenuate doxorubicin-induced cardiomyopathy. Sci Rep 5:11235. PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Koch JM, D’Souza SS, Schwahn DJ, Dixon I, Hacker TA (2016) Mesenchymoangioblast-derived mesenchymal stromal cells inhibit cell damage, tissue damage and improve peripheral blood flow following hindlimb ischemic injury in mice. Cytotherapy 18(2):219–228. PubMedCrossRefGoogle Scholar
  102. 102.
    Royce SG, Rele S, Broughton BRS, Kelly K, Samuel CS (2017) Intranasal administration of mesenchymoangioblast-derived mesenchymal stem cells abrogates airway fibrosis and airway hyperresponsiveness associated with chronic allergic airways disease. FASEB J 31(9):4168–4178. PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Wisconsin National Primate Research CenterUniversity of WisconsinMadisonUSA
  2. 2.Department of Cell and Regenerative Biology, School of Medicine and Public HealthUniversity of WisconsinMadisonUSA
  3. 3.Department of Pathology and Laboratory MedicineUniversity of WisconsinMadisonUSA

Personalised recommendations