Progress and prospects for stem cell engineering

Annual Review of Chemical and Biomolecular Engineering

Volumn 2, Issue , 2011, Pages 479-502

  Ashton, Randolph S ^a   Keung, Albert J ^a   Peltier, Joseph ^a   Schaffer, David V ^a,b,c  

^a University of California   (United States)

^b University of California at Berkeley   (United States)

^c UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

bioreactors; high throughput; microenvironment; systems and computational biology

Indexed keywords

BODY OF KNOWLEDGE; CELL ENGINEERING; CELL FATE DECISION; CELL REGULATION; CELL TYPES; CELLULAR SIGNALING; COMPLEX DATA; COMPUTATIONAL BIOLOGY; CULTURE SYSTEMS; EMPIRICAL KNOWLEDGE; HIGH-THROUGHPUT; INTRACELLULAR SIGNALING; MICROENVIRONMENTS; SCALE-UP; THEORETICAL APPROACH; THEORETICAL MODELING;

BIOINFORMATICS; ENGINEERS; ENZYME ACTIVITY; MACHINERY; SIGNALING; STEM CELLS; TISSUE;

CELL CULTURE;

ANIMAL; BIOLOGICAL THERAPY; CELL DIFFERENTIATION; CELL ENGINEERING; CHEMICAL MODEL; CYTOLOGY; HIGH THROUGHPUT SCREENING; HUMAN; METHODOLOGY; MICROARRAY ANALYSIS; PHYSIOLOGY; REVIEW; STEM CELL;

ANIMALS; CELL DIFFERENTIATION; CELL ENGINEERING; HIGH-THROUGHPUT SCREENING ASSAYS; HUMANS; MICROARRAY ANALYSIS; MODELS, CHEMICAL; STEM CELLS; TISSUE THERAPY;

EID: 79959478893     PISSN: 19475438     EISSN: None     Source Type: Journal    
DOI: 10.1146/annurev-chembioeng-061010-114105     Document Type: Article

References (150)

1. Becker AJ, Till JE, McCulloch EA. 1963. Cytological demonstration of clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nature 197:452-54
2. Evans MJ, Kaufman MH. 1981. Establishment in culture of pluripotential cells from mouse embryos. Nature 292:154-56 (Pubitemid 11050741)
3. Thomson JA, Itskovitz-Eldor J, Shapiro SS, WaknitzMA, Swiergiel JJ, et al. 1998. Embryonic stem cell lines derived from human blastocysts. Science 282:1145-47 (Pubitemid 28516247)
4. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, et al. 2007. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861-72 (Pubitemid 350138099)
5. Thomas ED, Lochte HL, Lu WC, Ferrebee JW. 1957. Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. N. Engl. J. Med. 257:491-96
6. Schofield R. 1978. Relationship between spleen colony-forming cell and hematopoietic stem-cell. Blood Cells 4:7-25 (Pubitemid 8376317)
7. Fernandes TG, Diogo MM, Clark DS, Dordick JS, Cabral JM. 2009. High-throughput cellular microarray platforms: Applications in drug discovery, toxicology and stem cell research. Trends Biotechnol. 27:342-49
8. Schena M, Shalon D, Davis RW, Brown PO. 1995. Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science 270:467-70
9. Yarmush ML, King KR. 2009. Living-cell microarrays. Annu. Rev. Biomed. Eng. 11:235-57
10. Bailey SN, Ali SM, Carpenter AE, Higgins CO, Sabatini DM. 2006. Microarrays of lentiviruses for gene function screens in immortalized and primary cells. Nat. Methods 3:117-22 (Pubitemid 43173310)
11. Flaim CJ, Chien S, Bhatia SN. 2005. An extracellular matrix microarray for probing cellular differentiation. Nat. Methods 2:119-25 (Pubitemid 41131033)
12. Brafman DA, ShahKD, Fellner T, Chien S,Willert K. 2009. Defining long-term maintenance conditions of human embryonic stem cells with arrayed cellular microenvironment technology. Stem Cells Dev. 18:1141-54
13. Yang J, Mei Y, Hook AL, Taylor M, Urquhart AJ, et al. 2010. Polymer surface functionalities that control human embryoid body cell adhesion revealed by high throughput surface characterization of combinatorial material microarrays. Biomaterials 31(34):8827-38
14. Mei Y, Saha K, Bogatyrev SR, Yang J,Hook AL, et al. 2010. Combinatorial development of biomaterials for clonal growth of human pluripotent stem cells. Nat. Mater. 9:768-78
15. Soen Y, Mori A, Palmer TD, Brown PO. 2006. Exploring the regulation of human neural precursor cell differentiation using arrays of signaling microenvironments. Mol. Syst. Biol. 2:37
16. Flaim CJ, Teng D, Chien S, Bhatia SN. 2008. Combinatorial signaling microenvironments for studying stem cell fate. Stem Cells Dev. 17:29-39 (Pubitemid 351271611)
17. Kane RS, Takayama S, Ostuni E, Ingber DE, Whitesides GM. 1999. Patterning proteins and cells using soft lithography. Biomaterials 20:2363-76
18. Whitesides GM, Ostuni E, Takayama S, Jiang X, Ingber DE. 2001. Soft lithography in biology and biochemistry. Annu. Rev. Biomed. Eng. 3:335-73 (Pubitemid 32928043)
19. Ashton RS, Peltier J, Fasano CA, O'Neill A, Leonard J, et al. 2007. High-throughput screening of gene function in stem cells using clonal microarrays. Stem Cells 25:2928-35 (Pubitemid 350127878)
20. McBeath R, Pirone DM, Nelson CM, Bhadriraju K, Chen CS. 2004. Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev. Cell 6:483-95 (Pubitemid 38456178)
21. Gao L, McBeath R, Chen CS. 2010. Stem cell shape regulates a chondrogenic versus myogenic fate through Rac1 and N-cadherin. Stem Cells 28:564-72
22. Nelson CM, Chen CS. 2003. VE-cadherin simultaneously stimulates and inhibits cell proliferation by altering cytoskeletal structure and tension. J. Cell Sci. 116:3571-81 (Pubitemid 37063400)
23. Khademhosseini A, Langer R, Borenstein J, Vacanti JP. 2006. Microscale technologies for tissue engineering and biology. Proc. Natl. Acad. Sci. USA 103:2480-87
24. Jeon N, Dertinger S, ChiuD, Choi I, Stroock A,WhitesidesG. 2000. Generation of solution and surface gradients using microfluidic systems. Langmuir 16:8311-16
25. Gomez-Sjoberg R, Leyrat AA, Pirone DM, Chen CS, Quake SR. 2007. Versatile, fully automated, microfluidic cell culture system. Anal. Chem. 79:8557-63 (Pubitemid 350171363)
26. Gupta K, Kim DH, Ellison D, Smith C, Kundu A, et al. 2010. Lab-on-a-chip devices as an emerging platform for stem cell biology. Lab Chip 10:2019-31
27. Peltier J, Schaffer DV. 2010. Systems biology approaches to understanding stem cell fate choice. IET Syst. Biol. 4:1-11
28. Lai K, Robertson MJ, Schaffer DV. 2004. The sonic hedgehog signaling system as a bistable genetic switch. Biophys. J. 86:2748-57 (Pubitemid 38552681)
29. Lai K, Kaspar BK, Gage FH, Schaffer DV. 2003. Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nat. Neurosci. 6:21-27 (Pubitemid 36026328)
30. Roeder I, Glauche I. 2006. Towards an understanding of lineage specification in hematopoietic stem cells: A mathematical model for the interaction of transcription factors GATA-1 and PU.1. J. Theor. Biol. 241:852-65 (Pubitemid 44080793)
31. Chickarmane V, Troein C, Nuber UA, Sauro HM, Peterson C. 2006. Transcriptional dynamics of the embryonic stem cell switch. PLoS Comput. Biol. 2:e123
32. Kim J, Chu J, Shen X,Wang J, Orkin SH. 2008. An extended transcriptional network for pluripotency of embryonic stem cells. Cell 132:1049-61 (Pubitemid 351381745)
33. Pardo M, Lang B, Yu L, Prosser H, Bradley A, et al. 2010. An expanded Oct4 interaction network: Implications for stem cell biology, development, and disease. Cell Stem Cell 6:382-95
34. Van Den Berg DL, Snoek T, Mullin NP, Yates A, Bezstarosti K, et al. 2010. An Oct4-centered protein interaction network in embryonic stem cells. Cell Stem Cell 6:369-81
35. Huang S, Guo YP, May G, Enver T. 2007. Bifurcation dynamics in lineage-commitment in bipotent progenitor cells. Dev. Biol. 305:695-713 (Pubitemid 46705410)
36. Agrawal S, Archer C, Schaffer DV. 2009. Computational models of the Notch network elucidate mechanisms of context-dependent signaling. PLoS Comput. Biol. 5:e1000390
37. Collier JR, Monk NA,Maini PK, Lewis JH. 1996. Pattern formation by lateral inhibition with feedback: A mathematical model of delta-notch intercellular signalling. J. Theor. Biol. 183:429-46 (Pubitemid 27033749)
38. WearingHJ, Owen MR, Sherratt JA. 2000. Mathematical modelling of juxtacrine patterning. Bull. Math. Biol. 62:293-320
39. Jensen MH, Sneppen K, Tiana G. 2003. Sustained oscillations and time delays in gene expression of protein Hes1. FEBS Lett. 541:176-77 (Pubitemid 36428938)
40. Monk NA. 2003. Oscillatory expression of Hes1, p53, andNF- ?B driven by transcriptional time delays. Curr. Biol. 13:1409-13 (Pubitemid 37029430)
41. Willerth SM, Sakiyama-Elbert SE. 2009. Kinetic analysis of neurotrophin-3-mediated differentiation of embryonic stem cells into neurons. Tissue Eng. Part A 15:307-18
42. Davey RE, Onishi K, Mahdavi A, Zandstra PW. 2007. LIF-mediated control of embryonic stem cell self-renewal emerges due to an autoregulatory loop. FASEB J. 21:2020-32 (Pubitemid 47026438)
43. Mahdavi A, Davey RE, Bhola P, Yin T, Zandstra PW. 2007. Sensitivity analysis of intracellular signaling pathway kinetics predicts targets for stem cell fate control. PLoS Comput. Biol. 3:e130
44. Kirouac DC, Zandstra PW. 2008. The systematic production of cells for cell therapies. Cell Stem Cell 3:369-81
45. Siminovitch L, McCulloch EA, Till JE. 1963. The distribution of colony-forming cells among spleen colonies. J. Cell Physiol. 62:327-36
46. Till JE,McCulloch EA, Siminovitch L. 1964. A stochastic model of stem cell proliferation, based on the growth of spleen colony-forming cells. Proc. Natl. Acad. Sci. USA 51:29-36
47. Till JE, McCulloch EA, Siminovitch L. 1964. Isolation of variant cell lines during serial transplantation of hematopoietic cells derived from fetal liver. J. Natl. Cancer Inst. 33:707-20
48. McAdams HH, Arkin A. 1997. Stochastic mechanisms in gene expression. Proc. Natl. Acad. Sci. USA 94:814-19 (Pubitemid 27074404)
49. Wilkinson DJ. 2009. Stochastic modelling for quantitative description of heterogeneous biological systems. Nat. Rev. Genet. 10:122-33
50. Raj A, van Oudenaarden A. 2008. Nature, nurture, or chance: Stochastic gene expression and its consequences. Cell 135:216-26
51. Graf T, Stadtfeld M. 2008. Heterogeneity of embryonic and adult stem cells. Cell Stem Cell 3:480-83
52. Chambers I, Silva J, Colby D, Nichols J, Nijmeijer B, et al. 2007. Nanog safeguards pluripotency and mediates germline development. Nature 450:1230-34
53. Chang HH, HembergM, BarahonaM, Ingber DE, Huang S. 2008. Transcriptome-wide noise controls lineage choice in mammalian progenitor cells. Nature 453:544-47 (Pubitemid 351733323)
54. Enver T, Pera M, Peterson C, Andrews PW. 2009. Stem cell states, fates, and the rules of attraction. Cell Stem Cell 4:387-97
55. Macarthur BD, Ma'ayan A, Lemischka IR. 2009. Systems biology of stem cell fate and cellular reprogramming. Nat. Rev. Mol. Cell Biol. 10:672-81
56. Huang S, Eichler G, Bar-Yam Y, Ingber DE. 2005. Cell fates as high-dimensional attractor states of a complex gene regulatory network. Phys. Rev. Lett. 94:128701
57. Chickarmane V, Enver T, Peterson C. 2009. Computational modeling of the hematopoietic erythroidmyeloid switch reveals insights into cooperativity, priming, and irreversibility. PLoS Comput. Biol. 5:e1000268
58. Woolf PJ, Prudhomme W, Daheron L, Daley GQ, Lauffenburger DA. 2005. Bayesian analysis of signaling networks governing embryonic stem cell fate decisions. Bioinformatics 21:741-53 (Pubitemid 40439410)
59. Janes KA, Yaffe MB. 2006. Data-driven modelling of signal-transduction networks. Nat. Rev. Mol. Cell Biol. 7:820-28 (Pubitemid 44627475)
60. Sharov AA, Piao Y, Matoba R, Dudekula DB, Qian Y, et al. 2003. Transcriptome analysis of mouse stem cells and early embryos. PLoS Biol. 1:E74
61. Aiba K, Sharov AA, Carter MG, Foroni C, Vescovi AL, KoMS. 2006. Defining a developmental path to neural fate by global expression profiling ofmouse embryonic stem cells and adult neural stem/progenitor cells. Stem Cells 24:889-95 (Pubitemid 44464722)
62. Prudhomme W, Daley GQ, Zandstra P, Lauffenburger DA. 2004. Multivariate proteomic analysis of murine embryonic stem cell self-renewal versus differentiation signaling. Proc. Natl. Acad. Sci. USA 101:2900-5 (Pubitemid 38327708)
63. Kalani MYS, Cheshier SH, Cord BJ, Bababeygy SR, Vogel H, et al. 2008. Wnt-mediated self-renewal of neural stem/progenitor cells. Proc. Natl. Acad. Sci. USA 105:16970-75
64. Bendall SC, Stewart MH, Menendez P, George D, Vijayaragavan K, et al. 2007. IGF and FGF cooperatively establish the regulatory stem cell niche of pluripotent human cells in vitro. Nature 448:1015-21 (Pubitemid 47345578)
65. Zandstra PW, Conneally E, Petzer AL, Piret JM, Eaves CJ. 1997. Cytokine manipulation of primitive human hematopoietic cell self-renewal. Proc. Natl. Acad. Sci. USA 94:4698-703
66. Zhang CC, Lodish HF. 2008. Cytokines regulating hematopoietic stem cell function. Curr. Opin. Hematol. 15:307-11
67. Martinez-Agosto JA, Mikkola HKA, Hartenstein V, Banerjee U. 2007. The hematopoietic stem cell and its niche: A comparative view. Genes Dev. 21:3044-60 (Pubitemid 350223522)
68. Suh H, Deng W, Gage FH. 2009. Signaling in adult neurogenesis. Annu. Rev. Cell Dev. Biol. 25:253-75
69. Williams DA, Rios M, Stephens C, Patel VP. 1991. Fibronectin and VLA-4 in haematopoietic stem cell-microenvironment interactions. Nature 352:438-41 (Pubitemid 21896743)
70. Frenette PS, Subbarao S, Mazo IB, von Andrian UH, Wagner DD. 1998. Endothelial selectins and vascular cell adhesion molecule-1 promote hematopoietic progenitor homing to bone marrow. Proc. Natl. Acad. Sci. USA 95:14423-28 (Pubitemid 28549383)
71. Papayannopoulou T, Nakamoto B. 1993. Peripheralization of hemopoietic progenitors in primates treated with anti-VLA4 integrin. Proc. Natl. Acad. Sci. USA 90:9374-78 (Pubitemid 23315786)
72. Rodin S, Domogatskaya A, Strom S, Hansson EM, Chien KR, et al. 2010. Long-term self-renewal of human pluripotent stem cells on human recombinant laminin-511. Nat. Biotechnol. 28:611-15
73. Hansen KC, Kiemele L, Maller O, O'Brien J, Shankar A, et al. 2009. An in-solution ultrasonicationassisted digestion method for improved extracellular matrix proteome coverage. Mol. Cell Proteomics 8:1648-57
74. Meng Y, Eshghi S, Li YJ, Schmidt R, Schaffer DV, Healy KE. 2010. Characterization of integrin engagement during defined human embryonic stem cell culture. FASEB J. 24:1056-65
75. Braam SR, Zeinstra L, Litjens S, Ward-van Oostwaard D, Van Den Brink S, et al. 2008. Recombinant vitronectin is a functionally defined substrate that supports human embryonic stem cell self-renewal via aVβ5 integrin. Stem Cells 26:2257-65
76. Melkoumian Z, Weber JL, Weber DM, Fadeev AG, Zhou Y, et al. 2010. Synthetic peptide-acrylate surfaces for long-term self-renewal and cardiomyocyte differentiation of human embryonic stem cells. Nat. Biotechnol. 28:606-10
77. Villa-Diaz LG, Nandivada H, Ding J, Nogueira-de-Souza NC, Krebsbach PH, et al. 2010. Synthetic polymer coatings for long-term growth of human embryonic stem cells. Nat. Biotechnol. 28:581-83
78. Pons S, Marti E. 2000. Sonic hedgehog synergizes with the extracellular matrix protein vitronectin to induce spinal motor neuron differentiation. Development 127:333-42 (Pubitemid 30087969)
79. Ye S, Luo Y, Lu W, Jones RB, Linhardt RJ, et al. 2001. Structural basis for interaction of FGF-1, FGF-2, and FGF-7 with different heparan sulfate motifs. Biochemistry 40:14429-39 (Pubitemid 33111725)
80. Kaartinen V,Warburton D. 2003. Fibrillin controls TGF-βactivation. Nat. Genet. 33:331-32
81. Ho JE, Chung EH, Wall S, Schaffer DV, Healy KE. 2007. Immobilized sonic hedgehog N-terminal signaling domain enhances differentiation of bone marrow-derived mesenchymal stem cells. J. Biomed. Mater. Res. A 83A:1200-8 (Pubitemid 350231783)
82. AlbertiK,Davey RE,OnishiK,George S, SalchertK, et al. 2008. Functional immobilization of signaling proteins enables control of stem cell fate. Nat. Methods 5:645-50 (Pubitemid 351911869)
83. Fan VH, Au A, Tamama K, Littrell R, Richardson LB, et al. 2007. Tethered epidermal growth factor provides a survival advantage to mesenchymal stem cells. Stem Cells 25:1241-51 (Pubitemid 46684884)
84. Salaita K, Nair PM, Petit RS, Neve RM, Das D, et al. 2010. Restriction of receptor movement alters cellular response: Physical force sensing by EphA2. Science 327:1380-85
85. Purtic B, Pitcher LA, van Oers NSC, Wülfing C. 2005. T cell receptor (TCR) clustering in the immunological synapse integrates TCR and costimulatory signaling in selected T cells. Proc. Natl. Acad. Sci. USA 102:2904-9 (Pubitemid 40299889)
86. Vyas N, Goswami D, Manonmani A, Sharma P, Ranganath HA, et al. 2008. Nanoscale organization of hedgehog is essential for long-range signaling. Cell 133:1214-27 (Pubitemid 351852915)
87. Fehon RG, Kooh PJ, Rebay I, Regan CL, Xu T, et al. 1990. Molecular interactions between the protein products of the neurogenic loci Notch and Delta, two EGF-homologous genes in Drosophila. Cell 61:523-34
88. Dean C, Scholl FG, Choih J, DeMaria S, Berger J, et al. 2003. Neurexin mediates the assembly of presynaptic terminals. Nat. Neurosci. 6:708-16 (Pubitemid 36792885)
89. Gordon WR, Vardar-Ulu D, Histen G, Sanchez-Irizarry C, Aster JC, Blacklow SC. 2007. Structural basis for autoinhibition of Notch. Nat. Struct. Mol. Biol. 14:295-300 (Pubitemid 46608349)
90. Varnum-Finney B,Wu L, YuM, Brashem-Stein C, Staats S, et al. 2000. Immobilization ofNotch ligand, Delta-1, is required for induction of notch signaling. J. Cell Sci. 113:4313-18 (Pubitemid 32000694)
91. Hicks C, Ladi E, Lindsell C, Hsieh JJ-D, Hayward SD, et al. 2002. A secreted Delta1-Fc fusion protein functions both as an activator and inhibitor of Notch1 signaling. J. Neurosci. Res. 68:655-67 (Pubitemid 34594983)
92. Morrison SJ, Perez SE, Qiao Z, Verdi JM, Hicks C, et al. 2000. Transient Notch activation initiates an irreversible switch from neurogenesis to gliogenesis by neural crest stem cells. Cell 101:499-510
93. Taqvi S,Dixit L, RoyK. 2006. Biomaterial-based notch signaling for the differentiation of hematopoietic stem cells into T cells. J. Biomed. Mater. Res. A 79A:689-97 (Pubitemid 44845184)
94. Delaney C, Varnum-FinneyB,AoyamaK,Brashem-Stein C, Bernstein ID. 2005. Dose-dependent effects of the Notch ligand Delta1 on ex vivo differentiation and in vivo marrow repopulating ability of cord blood cells. Blood 106:2693-99 (Pubitemid 41510742)
95. Wall ST, Saha K, Ashton RS, Kam KR, Schaffer DV, Healy KE. 2008. Multivalency of Sonic hedgehog conjugated to linear polymer chains modulates protein potency. Bioconjug. Chem. 19:806-12 (Pubitemid 351614536)
96. Treiser MD, Yang EH, Gordonov S, Cohen DM, Androulakis IP, et al. 2010. Cytoskeleton-based forecasting of stem cell lineage fates. Proc. Natl. Acad. Sci. USA 107:610-15
97. Ruiz SA,ChenCS. 2008. Emergence of patterned stem cell differentiationwithinmulticellular structures. Stem Cells 26:2921-27
98. Keller R, Davidson LA, Shook DR. 2003. How we are shaped: The biomechanics of gastrulation. Differentiation 71:171-205 (Pubitemid 36535222)
99. Engler AJ, Sen S, Sweeney HL,Discher DE. 2006. Matrix elasticity directs stem cell lineage specification. Cell 126:677-89 (Pubitemid 44233625)
100. Saha K, Keung AJ, Irwin EF, Li Y, Little L, et al. 2008. Substrate modulus directs neural stem cell behavior. Biophys. J. 95:4426-38
101. Saha S, Ji L, De Pablo J, Palecek S. 2008.TGFβ/activin/nodal pathway in inhibition of human embryonic stem cell differentiation by mechanical strain. Biophys. J. 94:4123-33
102. Chowdhury F, Na S, Li D, Poh Y-C, Tanaka TS, et al. 2010. Material properties of the cell dictate stress-induced spreading and differentiation in embryonic stem cells. Nat. Mater. 9:82-88
103. Wang H, Riha GM, Yan S, Li M, Chai H, et al. 2005. Shear stress induces endothelial differentiation from a murine embryonic mesenchymal progenitor cell line. Arterioscler. Thromb. Vasc. Biol. 25:1817-23 (Pubitemid 41243448)
104. Illi B, Scopece A, Nanni S, Farsetti A, Morgante L, et al. 2005. Epigenetic histone modification and cardiovascular lineage programming in mouse embryonic stem cells exposed to laminar shear stress. Circ. Res. 96:501-8 (Pubitemid 40463458)
105. Yamamoto K, Sokabe T, Watabe T, Miyazono K, Yamashita JK, et al. 2005. Fluid shear stress induces differentiation of Flk-1-positive embryonic stem cells into vascular endothelial cells in vitro. Am. J. Physiol. Heart Circ. Physiol. 288:H1915-24 (Pubitemid 40418021)
106. North TE, GoesslingW, Peeters M, Li P, Ceol C, et al. 2009. Hematopoietic stem cell development is dependent on blood flow. Cell 137:736-48
107. Adamo L, Naveiras O, Wenzel PL, McKinney-Freeman S, Mack PJ, et al. 2009. Biomechanical forces promote embryonic haematopoiesis. Nature 459:1131-35
108. Oh S, Brammer KS, Li YSJ, Teng D, Engler AJ, et al. 2009. Stem cell fate dictated solely by altered nanotube dimension. Proc. Natl. Acad. Sci. USA 106:2130-35
109. DalbyMJ, GadegaardN, Tare R, Andar A, Riehle MO, et al. 2007. The control of human mesenchymal cell differentiation using nanoscale symmetry and disorder. Nat. Mater. 6:997-1003 (Pubitemid 350210577)
110. Melkoumian Z, Weber JL, Weber DM, Fadeev AG, Zhou Y, et al. 2010. Synthetic peptide-acrylate surfaces for long-term self-renewal and cardiomyocyte differentiation of human embryonic stem cells. Nat. Biotechnol. 28:606-10
111. Murry CE, Reinecke H, Pabon LM. 2006. Regeneration gaps: Observations on stem cells and cardiac repair. J. Am. Coll. Cardiol. 47:1777-85
112. Lock LT, Tzanakakis ES. 2007. Stem/progenitor cell sources of insulin-producing cells for the treatment of diabetes. Tissue Eng. 13:1399-412 (Pubitemid 47105749)
113. Kehoe DE, Jing D, Lock LT, Tzanakakis ES. 2010. Scalable stirred-suspension bioreactor culture of human pluripotent stem cells. Tissue Eng. Part A 16:405-21
114. King JA, Miller WM. 2007. Bioreactor development for stem cell expansion and controlled differentiation. Curr. Opin. Chem. Biol. 11:394-98 (Pubitemid 47302847)
115. Dang SM,Gerecht-Nir S,Chen J, Itskovitz-Eldor J, Zandstra PW. 2004. Controlled, scalable embryonic stem cell differentiation culture. Stem Cells 22:275-82 (Pubitemid 38736612)
116. Serra M, Brito C, SousaMF, Jensen J, Tostoes R, et al. 2010. Improving expansion of pluripotent human embryonic stem cells in perfused bioreactors through oxygen control. J. Biotechnol. 148:208-15
117. Cormier JT, zur Nieden NI, Rancourt DE, Kallos MS. 2006. Expansion of undifferentiated murine embryonic stem cells as aggregates in suspension culture bioreactors. Tissue Eng. 12:3233-45 (Pubitemid 44846427)
118. Schroeder M, Niebruegge S, Werner A, Willbold E, Burg M, et al. 2005. Differentiation and lineage selection of mouse embryonic stem cells in a stirred bench scale bioreactor with automated process control. Biotechnol. Bioeng. 92:920-33
119. Hanna J, ChengAW,Saha K, Kim J,Lengner CJ, et al. 2010.Humanembryonic stem cells with biological and epigenetic characteristics similar to those of mouse ESCs. Proc. Natl. Acad. Sci. USA 107:9222-27
120. Watanabe K, Ueno M, Kamiya D, Nishiyama A,Matsumura M, et al. 2007. A ROCK inhibitor permits survival of dissociated human embryonic stem cells. Nat. Biotechnol. 25:681-86 (Pubitemid 46897207)
121. SteinerD, KhanerH, Cohen M, Even-Ram S,Gil Y, et al. 2010. Derivation, propagation and controlled differentiation of human embryonic stem cells in suspension. Nat. Biotechnol. 28:361-64
122. Amit M, Chebath J, Margulets V, Laevsky I, Miropolsky Y, et al. 2010. Suspension culture of undifferentiated human embryonic and induced pluripotent stem cells. Stem Cell Rev. 6:248-59
123. Singh H, Mok P, Balakrishnan T, Rahmat SN, Zweigerdt R. 2010. Up-scaling single cell-inoculated suspension culture of human embryonic stem cells. Stem Cell Res. 4:165-79
124. Lock LT, Tzanakakis ES. 2009. Expansion and differentiation of human embryonic stem cells to endoderm progeny in a microcarrier stirred-suspension culture. Tissue Eng. Part A 15:2051-63
125. Villa-Diaz LG, Nandivada H, Ding J, Nogueira-de-Souza NC, Krebsbach PH, et al. 2010. Synthetic polymer coatings for long-term growth of human embryonic stem cells. Nat. Biotechnol. 28:581-83
126. Lecina M, Ting S, Choo A, Reuveny S, Oh S. 2010. Scalable platform for human embryonic stem cell differentiation to cardiomyocytes in suspended microcarrier cultures. Tissue Eng. Part C 16:1609-19
127. Jing D, Parikh A, Tzanakakis ES. 2010. Cardiac cell generation from encapsulated embryonic stem cells in static and scalable culture systems. Cell Transplant. 19(11):1397-412
128. Gerecht S, Burdick JA, Ferreira LS, Townsend SA, Langer R, Vunjak-Novakovic G. 2007. Hyaluronic acid hydrogel for controlled self-renewal and differentiation of human embryonic stem cells. Proc. Natl. Acad. Sci. USA 104:11298-303 (Pubitemid 47175135)
129. Siti-Ismail N, Bishop AE, Polak JM, Mantalaris A. 2008. The benefit of human embryonic stem cell encapsulation for prolonged feeder-free maintenance. Biomaterials 29:3946-52
130. Gerecht-Nir S,Cohen S, Itskovitz-Eldor J. 2004. Bioreactor cultivation enhances the efficiency of human embryoid body (hEB) formation and differentiation. Biotechnol. Bioeng. 86:493-502 (Pubitemid 38679767)
131. Yirme G, Amit M, Laevsky I, Osenberg S, Itskovitz-Eldor J. 2008. Establishing a dynamic process for the formation, propagation, and differentiation of human embryoid bodies. Stem Cells Dev. 17:1227-41
132. Cameron CM, Hu WS, Kaufman DS. 2006. Improved development of human embryonic stem cellderived embryoid bodies by stirred vessel cultivation. Biotechnol. Bioeng. 94:938-48 (Pubitemid 44186901)
133. Sachlos E, Auguste DT. 2008. Embryoid body morphology influences diffusive transport of inductive biochemicals: A strategy for stem cell differentiation. Biomaterials 29:4471-80
134. Bratt-Leal AM,Carpenedo RL,McDevitt TC. 2009. Engineering the embryoid body microenvironment to direct embryonic stem cell differentiation. Biotechnol. Prog. 25:43-51
135. Bauwens CL, Peerani R, Niebruegge S, Woodhouse KA, Kumacheva E, et al. 2008. Control of human embryonic stem cell colony and aggregate size heterogeneity influences differentiation trajectories. Stem Cells 26:2300-10
136. Lee LH, Peerani R, Ungrin M, Joshi C, Kumacheva E, Zandstra P. 2009. Micropatterning of human embryonic stem cells dissects the mesoderm and endoderm lineages. Stem Cell Res. 2:155-62
137. Niebruegge S, Bauwens CL, Peerani R, Thavandiran N, Masse S, et al. 2009. Generation of human embryonic stem cell-derived mesoderm and cardiac cells using size-specified aggregates in an oxygencontrolled bioreactor. Biotechnol. Bioeng. 102:493-507
138. Hwang YS, Chung BG, Ortmann D, Hattori N, Moeller HC, Khademhosseini A. 2009. Microwellmediated control of embryoid body size regulates embryonic stem cell fate via differential expression of WNT5a and WNT11. Proc. Natl. Acad. Sci. USA 106:16978-83
139. Ng ES, Davis RP, Azzola L, Stanley EG, Elefanty AG. 2005. Forced aggregation of defined numbers of human embryonic stem cells into embryoid bodies fosters robust, reproducible hematopoietic differentiation. Blood 106:1601-3 (Pubitemid 41208571)
140. Burridge PW, Anderson D, Priddle H, Barbadillo Munoz MD, Chamberlain S, et al. 2007. Improved human embryonic stem cell embryoid body homogeneity and cardiomyocyte differentiation from a novel V-96 plate aggregation system highlights interline variability. Stem Cells 25:929-38 (Pubitemid 46572590)
141. Ungrin MD, Joshi C, Nica A, Bauwens C, Zandstra PW. 2008. Reproducible, ultra high-throughput formation of multicellular organization from single cell suspension-derived human embryonic stem cell aggregates. PLoS ONE 3:e1565
142. Carpenedo RL, Bratt-Leal AM, Marklein RA, Seaman SA, Bowen NJ, et al. 2009. Homogeneous and organized differentiation within embryoid bodies induced by microsphere-mediated delivery of small molecules. Biomaterials 30:2507-15
143. Carpenedo RL, Seaman SA, McDevitt TC. 2010. Microsphere size effects on embryoid body incorporation and embryonic stem cell differentiation. J. Biomed. Mater. Res. A 94:466-75
144. Ferreira L, Squier T, Park H, Choe H, Kohane DS, Langer R. 2008. Human embryoid bodies containing nano- and, icroparticulate delivery vehicles. Adv. Mater. 20:2285-91
145. BielinskaM, Narita N,Wilson DB. 1999. Distinct roles for visceral endoderm during embryonic mouse development. Int. J. Dev. Biol. 43:183-205 (Pubitemid 29268337)
146. Bai H, Gao Y, Arzigian M, Wojchowski DM, Wu WS, Wang ZZ. 2010. BMP4 regulates vascular progenitor development in human embryonic stem cells through a Smad-dependent pathway. J. Cell. Biochem. 109:363-74
147. Chambers SM, Fasano CA, Papapetrou EP, Tomishima M, Sadelain M, Studer L. 2009. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat. Biotechnol. 27:275-80
148. Laflamme MA, Chen KY, Naumova AV, Muskheli V, Fugate JA, et al. 2007. Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat. Biotechnol. 25:1015-24 (Pubitemid 47517637)
149. Borowiak M, Maehr R, Chen S, Chen AE, Tang W, et al. 2009. Small molecules efficiently direct endodermal differentiation of mouse and human embryonic stem cells. Cell Stem Cell 4:348-58
150. Chayosumrit M, Tuch B, Sidhu K. 2010. Alginate microcapsule for propagation and directed differentiation of hESCs to definitive endoderm. Biomaterials 31:505-14