title: Mechanical Forces Reshape Differentiation Cues That Guide Cardiomyogenesis.
abstract: Soluble morphogen gradients have long been studied in the context of heart specification and patterning. However, recent data have begun to challenge the notion that long-standing in vivo observations are driven solely by these gradients alone. Evidence from multiple biological models, from stem cells to ex vivo biophysical assays, now supports a role for mechanical forces in not only modulating cell behavior but also inducing it de novo in a process termed mechanotransduction. Structural proteins that connect the cell to its niche, for example, integrins and cadherins, and that couple to other growth factor receptors, either directly or indirectly, seem to mediate these changes, although specific mechanistic details are still being elucidated. In this review, we summarize how the wingless (Wnt), transforming growth factor-β, and bone morphogenetic protein signaling pathways affect cardiomyogenesis and then highlight the interplay between each pathway and mechanical forces. In addition, we will outline the role of integrins and cadherins during cardiac development. For each, we will describe how the interplay could change multiple processes during cardiomyogenesis, including the specification of undifferentiated cells, the establishment of heart patterns to accomplish tube and chamber formation, or the maturation of myocytes in the fully formed heart.
authors.affiliation: From the Department of Bioengineering, University of California, San Diego, La Jolla; and Sanford Consortium for Regenerative Medicine, La Jolla, CA.
authors.forename: Cassandra L
authors.initials: CL
authors.lastname: Happe
authors.affiliation: From the Department of Bioengineering, University of California, San Diego, La Jolla; and Sanford Consortium for Regenerative Medicine, La Jolla, CA. aengler@ucsd.edu.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Engler
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation; D005865:Gestational Age; D006321:Heart / Q000196:embryology*; D006801:Humans; D016023:Integrins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D040542:Mechanotransduction, Cellular; D038081:Organogenesis; D013234:Stem Cells / Q000378:metabolism*; D013314:Stress, Mechanical; D016212:Transforming Growth Factor beta / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D019485:Bone Morphogenetic Proteins; D015820:Cadherins; D016023:Integrins; D036341:Intercellular Signaling Peptides and Proteins; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins
keywords: cadherins; heart; integrins; stem cells; transforming growth factor
references.citation: Am J Physiol Renal Physiol. 2002 Feb;282(2):F179-90
references.pmid: 11788431
references.citation: Sci Signal. 2009;2(66):ra16
references.pmid: 19366994
references.citation: PLoS One. 2012;7(5):e37802
references.pmid: 22666394
references.citation: J Cell Sci. 2008 Nov 15;121(Pt 22):3794-802
references.pmid: 18957515
references.citation: Curr Biol. 2003 Aug 19;13(16):1365-77
references.pmid: 12932320
references.citation: Cell Res. 2009 Jan;19(1):58-70
references.pmid: 19050695
references.citation: Tissue Eng Part A. 2008 Jan;14(1):49-58
references.pmid: 18333804
references.citation: Cell Stem Cell. 2012 Jan 6;10(1):16-28
references.pmid: 22226352
references.citation: Genes Dev. 2001 Nov 1;15(21):2797-802
references.pmid: 11691831
references.citation: Development. 1993 Dec;119(4):1093-105
references.pmid: 7508365
references.citation: Biomaterials. 2010 Mar;31(7):1885-93
references.pmid: 19945747
references.citation: Development. 1994 Jul;120(7):1919-28
references.pmid: 7924997
references.citation: Development. 2009 Feb;136(4):665-76
references.pmid: 19168680
references.citation: Am J Physiol. 1997 Aug;273(2 Pt 2):H546-56
references.pmid: 9277468
references.citation: Cell Stem Cell. 2007 Aug 16;1(2):165-79
references.pmid: 18371348
references.citation: Dev Biol. 1997 Jan 1;181(1):64-78
references.pmid: 9015265
references.citation: Mol Cell Endocrinol. 2015 Jan 5;399:9-21
references.pmid: 25218476
references.citation: Cell Mol Life Sci. 2010 Jan;67(2):277-90
references.pmid: 19844658
references.citation: Stem Cell Res. 2007 Nov;1(2):138-49
references.pmid: 19383394
references.citation: Int J Cell Biol. 2012;2012:508294
references.pmid: 22649451
references.citation: Annu Rev Cell Dev Biol. 2007;23:45-68
references.pmid: 17456019
references.citation: Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9770-5
references.pmid: 23716679
references.citation: Cell Stem Cell. 2008 Jul 3;3(1):55-68
references.pmid: 18593559
references.citation: Circ Res. 2005 Feb 18;96(3):292-9
references.pmid: 15637299
references.citation: Ann Biomed Eng. 2011 Jun;39(6):1840-7
references.pmid: 21336802
references.citation: Nat Cell Biol. 2008 Mar;10(3):338-45
references.pmid: 18297060
references.citation: Nat Mater. 2014 Jun;13(6):547-57
references.pmid: 24845994
references.citation: Dev Cell. 2002 Sep;3(3):311-21
references.pmid: 12361595
references.citation: Biochim Biophys Acta. 2012 Dec;1824(12):1374-81
references.pmid: 22824487
references.citation: Dev Cell. 2007 Jul;13(1):10-3
references.pmid: 17609106
references.citation: Sci Rep. 2014;4:6425
references.pmid: 25236849
references.citation: Cardiovasc Res. 2014 Jun 1;102(3):407-17
references.pmid: 24639195
references.citation: Nat Rev Cardiol. 2013 Sep;10(9):531-47
references.pmid: 23900355
references.citation: Cardiovasc Res. 2010 Jan 1;85(1):100-9
references.pmid: 19622544
references.citation: Nat Genet. 2007 Oct;39(10):1225-34
references.pmid: 17767158
references.citation: Nature. 2003 Jan 9;421(6919):172-7
references.pmid: 12520305
references.citation: Biophys J. 2008 May 15;94(10):4123-33
references.pmid: 18234825
references.citation: Acta Biomater. 2014 Feb;10(2):604-12
references.pmid: 24200714
references.citation: Anat Embryol (Berl). 2002 Oct;205(5-6):343-54
references.pmid: 12382138
references.citation: Development. 2010 May;137(9):1407-20
references.pmid: 20388652
references.citation: Circ Res. 2005 Mar 18;96(5):501-8
references.pmid: 15705964
references.citation: Differentiation. 1999 Mar;64(3):173-84
references.pmid: 10234814
references.citation: Exp Biol Med (Maywood). 2011 Jul;236(7):816-22
references.pmid: 21680756
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 5;104(23):9685-90
references.pmid: 17522258
references.citation: Stem Cells. 2007 Sep;25(9):2224-34
references.pmid: 17585171
references.citation: Circ Res. 2005 Dec 9;97(12):1220-31
references.pmid: 16339494
references.citation: Science. 2009 May 15;324(5929):941-4
references.pmid: 19359542
references.citation: Nat Cell Biol. 2009 Aug;11(8):951-7
references.pmid: 19620969
references.citation: Biol Cell. 2004 Sep;96(7):471-7
references.pmid: 15380614
references.citation: Development. 2006 Jun;133(12):2435-45
references.pmid: 16720880
references.citation: Am J Physiol Heart Circ Physiol. 2006 Jun;290(6):H2196-203
references.pmid: 16473959
references.citation: Biomech Model Mechanobiol. 2012 Nov;11(8):1227-39
references.pmid: 22772714
references.citation: Development. 2008 Mar;135(6):1029-37
references.pmid: 18256196
references.citation: Dev Biol. 2006 May 15;293(2):305-15
references.pmid: 16563368
references.citation: Genes Dev. 2009 Feb 1;23(3):265-77
references.pmid: 19204114
references.citation: Biofactors. 2014 Mar-Apr;40(2):171-87
references.pmid: 24123658
references.citation: Biotechnol Bioeng. 2002 May 20;78(4):442-53
references.pmid: 11948451
references.citation: Genes Dev. 2005 Feb 1;19(3):387-96
references.pmid: 15687261
references.citation: Curr Biol. 1999 Mar 11;9(5):277-80
references.pmid: 10074453
references.citation: Biomaterials. 2011 Feb;32(4):1002-9
references.pmid: 21071078
references.citation: Nat Rev Mol Cell Biol. 2005 Aug;6(8):622-34
references.pmid: 16025097
references.citation: Cell Stem Cell. 2012 Aug 3;11(2):242-52
references.pmid: 22862949
references.citation: Nat Rev Mol Cell Biol. 2009 Feb;10(2):91-103
references.pmid: 19129791
references.citation: J Cell Biochem. 2011 Jul;112(7):1880-9
references.pmid: 21433060
references.citation: Stem Cells. 2013 Jun;31(6):1213-7
references.pmid: 23417899
references.citation: Curr Opin Cell Biol. 2008 Oct;20(5):520-4
references.pmid: 18603422
references.citation: Curr Opin Cell Biol. 2009 Oct;21(5):616-22
references.pmid: 19525102
references.citation: Nature. 2001 Oct 25;413(6858):797-803
references.pmid: 11677596
references.citation: Oncogene. 2004 Nov 4;23(52):8520-6
references.pmid: 15378020
references.citation: Nat Cell Biol. 2000 Feb;2(2):76-83
references.pmid: 10655586
references.citation: J Cell Biol. 2014 Oct 27;207(2):283-97
references.pmid: 25332161
references.citation: Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9482-7
references.pmid: 12874388
references.citation: Dev Biol. 1998 Sep 15;201(2):167-84
references.pmid: 9740657
references.citation: J Cardiovasc Transl Res. 2011 Oct;4(5):605-15
references.pmid: 21744185
references.citation: J Cell Physiol. 2006 Jan;206(1):126-37
references.pmid: 15965964
references.citation: Biomaterials. 2012 Mar;33(7):2041-9
references.pmid: 22177620
references.citation: Development. 2005 Sep;132(18):4165-78
references.pmid: 16123312
references.citation: Cell. 1996 May 31;85(5):683-93
references.pmid: 8646777
references.citation: Development. 2004 May;131(9):2219-31
references.pmid: 15073151
references.citation: Proc Natl Acad Sci U S A. 2011 Jun 7;108(23):9466-71
references.pmid: 21593411
references.citation: Development. 2009 Mar;136(5):701-13
references.pmid: 19201946
references.citation: Biomaterials. 2008 Mar;29(7):844-56
references.pmid: 18022225
references.citation: J Mol Cell Cardiol. 2001 Mar;33(3):521-32
references.pmid: 11181020
references.citation: Development. 2005 Feb;132(3):479-90
references.pmid: 15634695
references.citation: Dev Cell. 2009 Mar;16(3):329-43
references.pmid: 19289080
references.citation: Development. 2015 Feb 15;142(4):692-701
references.pmid: 25670794
references.citation: Nat Rev Mol Cell Biol. 2009 Jan;10(1):75-82
references.pmid: 19197334
references.citation: Swiss Med Wkly. 2009 Mar 7;139(9-10):122-34
references.pmid: 19274489
references.citation: Basic Res Cardiol. 2008 Nov;103(6):514-24
references.pmid: 18500484
references.citation: Science. 2004 Mar 5;303(5663):1483-7
references.pmid: 15001769
references.citation: Biochem J. 1996 Jan 1;313 ( Pt 1):343-51
references.pmid: 8546705
references.citation: Nat Cell Biol. 2012 Sep;14(9):935-43
references.pmid: 22885771
references.citation: Curr Biol. 2006 Oct 24;16(20):1986-97
references.pmid: 17055977
references.citation: Lab Invest. 2002 Jan;82(1):37-46
references.pmid: 11796824
references.citation: Biophys J. 2004 Jan;86(1 Pt 1):617-28
references.pmid: 14695306
references.citation: Genes Dev. 1991 Sep;5(9):1568-76
references.pmid: 1884999
references.citation: Pflugers Arch. 2011 Jul;462(1):89-104
references.pmid: 21499986
references.citation: Circ Res. 2002 Mar 8;90(4):458-64
references.pmid: 11884376
references.citation: Nature. 2008 Jul 17;454(7202):345-9
references.pmid: 18528331
references.citation: Eur J Cell Biol. 2008 Sep;87(8-9):601-15
references.pmid: 18342983
references.citation: J Cell Biol. 2007 Dec 17;179(6):1311-23
references.pmid: 18086923
references.citation: Tissue Eng Part A. 2009 Feb;15(2):331-42
references.pmid: 19193130
references.citation: Dev Biol. 2010 May 1;341(1):5-19
references.pmid: 19751720
references.citation: Development. 1996 Oct;122(10):2977-86
references.pmid: 8898212
references.citation: Pediatr Res. 2007 Apr;61(4):386-91
references.pmid: 17515859
references.citation: Genes Dev. 2009 Feb 15;23(4):397-418
references.pmid: 19240129
references.citation: Development. 1999 Aug;126(15):3437-47
references.pmid: 10393122
references.citation: Cold Spring Harb Perspect Biol. 2010 Dec;2(12):a005066
references.pmid: 21084386
references.citation: Annu Rev Cell Dev Biol. 2014;30:291-315
references.pmid: 25062360
references.citation: BMC Cell Biol. 2013;14:5
references.pmid: 23350814
references.citation: Dev Biol. 2013 Sep 1;381(1):73-82
references.pmid: 23791818
references.citation: Circ Res. 2014 Jan 31;114(3):572-86
references.pmid: 24481847
references.citation: Front Endocrinol (Lausanne). 2015 Jan 20;5:246
references.pmid: 25653639
references.citation: Trends Cardiovasc Med. 1994 Jul-Aug;4(4):178-87
references.pmid: 21244884
references.citation: Mech Dev. 1998 Jan;70(1-2):119-31
references.pmid: 9510029
references.citation: J Biomech. 2012 Mar 15;45(5):832-41
references.pmid: 22236531
references.citation: Dev Biol. 2000 Sep 1;225(1):214-25
references.pmid: 10964476
references.citation: Curr Biol. 2011 Dec 20;21(24):2046-54
references.pmid: 22169532
references.citation: Cardiovasc Res. 2012 Dec 1;96(3):352-62
references.pmid: 22893679
references.citation: Genes Dev. 1999 Jul 15;13(14):1834-46
references.pmid: 10421635
references.citation: Biotechnol Bioeng. 2010 Feb 15;105(3):611-26
references.pmid: 19816980
references.citation: Dev Biol. 2005 Feb 1;278(1):255-63
references.pmid: 15649477
references.citation: Trends Cell Biol. 2010 May;20(5):244-56
references.pmid: 20188563
references.citation: Mol Cell Biol. 2001 Dec;21(23):8184-8
references.pmid: 11689706
references.citation: Ann Biomed Eng. 2003 Dec;31(11):1327-36
references.pmid: 14758923
references.citation: Nature. 2011 Jun 16;474(7351):343-9
references.pmid: 21677751
references.citation: J Cell Biol. 2000 Jul 10;150(1):225-41
references.pmid: 10893270
references.citation: Curr Opin Cell Biol. 1991 Oct;3(5):841-8
references.pmid: 1931084
references.citation: Biomaterials. 2012 Mar;33(7):2032-40
references.pmid: 22169822
references.citation: Curr Opin Cell Biol. 2011 Feb;23(1):30-8
references.pmid: 21130639
references.citation: Dev Biol. 2003 Jun 1;258(1):1-19
references.pmid: 12781678
references.citation: Genes Dev. 1995 Sep 1;9(17):2105-16
references.pmid: 7657163
references.citation: Nat Biotechnol. 2005 May;23(5):607-11
references.pmid: 15867910
references.citation: Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19812-7
references.pmid: 17170140
references.citation: Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):12141-5
references.pmid: 8618860
references.citation: Mol Biol Cell. 2004 Nov;15(11):5012-20
references.pmid: 15356272
references.citation: PLoS One. 2011;6(8):e23272
references.pmid: 21858051
references.citation: J Biol Chem. 2006 Nov 10;281(45):34021-31
references.pmid: 16966322
references.citation: Nat Med. 2006 Apr;12(4):452-8
references.pmid: 16582915
references.citation: Circ Res. 2010 Jul 23;107(2):186-99
references.pmid: 20651295
references.citation: Nat Cell Biol. 2013 Aug;15(8):926-36
references.pmid: 23831726
references.citation: Cell Mol Biol Res. 1995;41(4):233-40
references.pmid: 8775981
references.citation: Development. 1995 Feb;121(2):549-60
references.pmid: 7539359
references.citation: Mol Cell Biol. 2006 Oct;26(20):7791-805
references.pmid: 16923969
references.citation: Cell. 2006 Aug 25;126(4):677-89
references.pmid: 16923388
references.citation: Cell. 1998 Dec 11;95(6):829-37
references.pmid: 9865700
references.citation: Circ Res. 2010 Dec 10;107(12):1414-27
references.pmid: 21148448
references.citation: Cell. 1994 Mar 25;76(6):1075-89
references.pmid: 8137424
references.citation: J Mol Cell Cardiol. 2012 Mar;52(3):650-9
references.pmid: 22146296
references.citation: Int J Dev Biol. 2000 Apr;44(3):253-65
references.pmid: 10853822
references.citation: Development. 1997 May;124(9):1631-42
references.pmid: 9165112
references.citation: Dev Cell. 2006 Sep;11(3):313-23
references.pmid: 16950123
references.citation: Biophys J. 2008 Oct;95(7):3479-87
references.pmid: 18586852
references.citation: Biochem J. 2003 Jan 15;369(Pt 2):311-8
references.pmid: 12358597
references.citation: Genes Dev. 1998 Apr 15;12(8):1202-16
references.pmid: 9553049
references.citation: Nat Rev Mol Cell Biol. 2009 Jan;10(1):34-43
references.pmid: 19197330
references.citation: Genes Dev. 1995 Aug 1;9(15):1883-95
references.pmid: 7544312
references.citation: Nature. 2005 May 12;435(7039):172-7
references.pmid: 15889083
references.citation: Nat Rev Mol Cell Biol. 2007 Nov;8(11):857-69
references.pmid: 17895899
references.citation: Am J Physiol Heart Circ Physiol. 2005 Dec;289(6):H2291-301
references.pmid: 16284104
references.citation: J Mol Cell Cardiol. 2005 Mar;38(3):495-503
references.pmid: 15733909
references.citation: Circ Res. 2012 Oct 12;111(9):1125-36
references.pmid: 22912385
references.citation: Dev Biol. 2001 Jul 15;235(2):449-66
references.pmid: 11437450
references.citation: Nat Rev Genet. 2000 Dec;1(3):171-81
references.pmid: 11252746
references.citation: Stem Cells Dev. 2013 Oct 1;22(19):2665-77
references.pmid: 23767804
references.citation: Nature. 2002 Aug 8;418(6898):636-41
references.pmid: 12167861
references.citation: Circ Res. 2012 Sep 14;111(7):876-81
references.pmid: 22872153
references.citation: Genes Dev. 1997 Feb 15;11(4):451-62
references.pmid: 9042859
references.citation: Annu Rev Cell Dev Biol. 2011;27:377-407
references.pmid: 21801015
references.citation: J Cell Sci. 1996 Dec;109 ( Pt 13):2989-99
references.pmid: 9004034
references.citation: Stem Cells. 2015 Apr;33(4):1021-35
references.pmid: 25537366
references.citation: Nature. 2008 Sep 4;455(7209):72-7
references.pmid: 18701888
references.citation: Curr Opin Cell Biol. 2011 Oct;23(5):523-30
references.pmid: 21890337
references.citation: Curr Opin Genet Dev. 2007 Aug;17(4):281-6
references.pmid: 17624758