Embryonic stem cells (ESCs) emerge as a promising tool for tissue engineering and regenerative medicines due to their extensive self-renewal ability and the capacity to give rise to cells from all three-germ layers. ESCs also secrete a large amount of endogenous extracellular matrices (ECMs), which play an important role in regulating ESC self-renewal, lineage commitment, and tissue morphogenesis. ECMs derived from ESCs have a broader signaling capacity compared to somatic ECMs and are predicted to have a lower risk of tumor formation associated with ESCs. In this study, ECMs from undifferentiated ESC monolayers, undifferentiated aggregates, or differentiated embryoid bodies at different developmental stages and lineage specifications were decellularized and their capacities to direct ESC proliferation and differentiation were characterized. The results demonstrate that the ESC-derived ECMs were able to influence ESC proliferation and differentiation by direct interactions with the cells and by influencing the signaling functions of the regulatory macromolecules such as retinoic acid. Such matrices have the potential to present regulatory signals to direct lineage- and development-specific cellular responses for in vitro applications or cell delivery.
Get full access to this article
View all access options for this article.
References
1.
ThomsonJ.A., Itskovitz-EldorJ., ShapiroS.S., WaknitzM.A., SwiergielJ.J., MarshallV.S., and JonesJ.M.Embryonic stem cell lines derived from human blastocysts. Science, 282, 1145, 1998.
2.
TakahashiK., TanabeK., OhnukiM., NaritaM., IchisakaT., TomodaK., and YamanakaS.Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131, 861, 2007.
3.
YuJ., VodyanikM.A., Smuga-OttoK., Antosiewicz-BourgetJ., FraneJ.L., TianS., NieJ., JonsdottirG.A., RuottiV., StewartR., SlukvinI.I., and ThomsonJ.A.Induced pluripotent stem cell lines derived from human somatic cells. Science, 318, 1917, 2007.
4.
RozarioT., and DeSimoneD.W.The extracellular matrix in development and morphogenesis: a dynamic view. Dev Biol, 341, 126, 2010.
5.
HynesR.O.The extracellular matrix: not just pretty fibrils. Science, 326, 1216, 2009.
6.
HughesC., RadanL., ChangW.Y., StanfordW.L., BettsD.H., PostovitL.M., and LajoieG.A.Mass spectrometry-based proteomics analysis of the matrix microenvironment in pluripotent stem cell culture. Mol Cell Proteomics, 11, 1924, 2012.
7.
HuntG.C., SinghP., and SchwarzbauerJ.E.Endogenous production of fibronectin is required for self-renewal of cultured mouse embryonic stem cells. Exp Cell Res, 318, 1820, 2012.
8.
ChenS.S., FitzgeraldW., ZimmerbergJ., KleinmanH.K., and MargolisL.Cell-cell and cell-extracellular matrix interactions regulate embryonic stem cell differentiation. Stem Cells, 25, 553, 2007.
9.
PrzybylaL., and VoldmanJ.Probing embryonic stem cell autocrine and paracrine signaling using microfluidics. Annu Rev Anal Chem (Palo Alto Calif), 5, 293, 2012.
10.
NairR., NganganA.V., KempM.L., and McDevittT.C.Gene expression signatures of extracellular matrix and growth factors during embryonic stem cell differentiation. PLoS One, 7, e42580, 2012.
11.
NairR., ShuklaS., and McDevittT.C.Acellular matrices derived from differentiating embryonic stem cells. J Biomed Mater Res A, 87, 1075, 2008.
12.
NganganA.V., and McDevittT.C.Acellularization of embryoid bodies via physical disruption methods. Biomaterials, 30, 1143, 2009.
13.
ChoiJ.S., YangH.J., KimB.S., KimJ.D., KimJ.Y., YooB., ParkK., LeeH.Y., and ChoY.W.Human extracellular matrix (ECM) powders for injectable cell delivery and adipose tissue engineering. J Control Release, 139, 2, 2009.
14.
TurnerA.E., and FlynnL.E.Design and characterization of tissue-specific extracellular matrix-derived microcarriers. Tissue Eng Part C Methods, 18, 186, 2012.
15.
TurnerA.E., YuC., BiancoJ., WatkinsJ.F., and FlynnL.E.The performance of decellularized adipose tissue microcarriers as an inductive substrate for human adipose-derived stem cells. Biomaterials, 33, 4490, 2012.
16.
LuH., HoshibaT., KawazoeN., and ChenG.Autologous extracellular matrix scaffolds for tissue engineering. Biomaterials, 32, 2489, 2011.
17.
KimJ., and MaT.Autocrine fibroblast growth factor 2-mediated interactions between human mesenchymal stem cells and the extracellular matrix under varying oxygen tension. J Cell Biochem, 114, 716, 2013.
18.
SartS., ErrachidA., SchneiderY.J., and AgathosS.N.Modulation of mesenchymal stem cell actin organization on conventional microcarriers for proliferation and differentiation in stirred bioreactors. J Tissue Eng Regen Med, 7, 537, 2013.
19.
LockL.T., and TzanakakisE.S.Expansion and differentiation of human embryonic stem cells to endoderm progeny in a microcarrier stirred-suspension culture. Tissue Eng Part A, 15, 2051, 2009.
20.
PostovitL.M., MargaryanN.V., SeftorE.A., KirschmannD.A., LipavskyA., WheatonW.W., AbbottD.E., SeftorR.E., and HendrixM.J.Human embryonic stem cell microenvironment suppresses the tumorigenic phenotype of aggressive cancer cells. Proc Natl Acad Sci U S A, 105, 4329, 2008.
21.
PostovitL.M., SeftorE.A., SeftorR.E., and HendrixM.J.A three-dimensional model to study the epigenetic effects induced by the microenvironment of human embryonic stem cells. Stem Cells, 24, 501, 2006.
22.
FokE.Y., and ZandstraP.W.Shear-controlled single-step mouse embryonic stem cell expansion and embryoid body-based differentiation. Stem Cells, 23, 1333, 2005.
23.
Bratt-LealA.M., CarpenedoR.L., and McDevittT.C.Engineering the embryoid body microenvironment to direct embryonic stem cell differentiation. Biotechnol Prog, 25, 43, 2009.
24.
XuC., InokumaM.S., DenhamJ., GoldsK., KunduP., GoldJ.D., and CarpenterM.K.Feeder-free growth of undifferentiated human embryonic stem cells. Nat Biotechnol, 19, 971, 2001.
25.
ZweigerdtR., OlmerR., SinghH., HaverichA., and MartinU.Scalable expansion of human pluripotent stem cells in suspension culture. Nat Protoc, 6, 689, 2011.
26.
AzarinS.M., LianX., LarsonE.A., PopelkaH.M., de PabloJ.J., and PalecekS.P.Modulation of Wnt/beta-catenin signaling in human embryonic stem cells using a 3-D microwell array. Biomaterials, 33, 2041, 2012.
27.
KraushaarD.C., RaiS., CondacE., NairnA., ZhangS., YamaguchiY., MoremenK., DaltonS., and WangL.Heparan sulfate facilitates FGF and BMP signaling to drive mesoderm differentiation of mouse embryonic stem cells. J Biol Chem, 287, 22691, 2012.
28.
FarinaA., D'AnielloC., SeverinoV., HochstrasserD.F., ParenteA., MinchiottiG., and ChamberyA.Temporal proteomic profiling of embryonic stem cell secretome during cardiac and neural differentiation. Proteomics, 11, 3972, 2011.
29.
SachlosE., and AugusteD.T.Embryoid body morphology influences diffusive transport of inductive biochemicals: a strategy for stem cell differentiation. Biomaterials, 29, 4471, 2008.
30.
UlloaL., and TabibzadehS.Lefty inhibits receptor-regulated Smad phosphorylation induced by the activated transforming growth factor-beta receptor. J Biol Chem, 276, 21397, 2001.
31.
ZhangP., LiJ., TanZ., WangC., LiuT., ChenL., YongJ., JiangW., SunX., DuL., DingM., and DengH.Short-term BMP-4 treatment initiates mesoderm induction in human embryonic stem cells. Blood, 111, 1933, 2008.
32.
OkadaY., ShimazakiT., SobueG., and OkanoH.Retinoic-acid-concentration-dependent acquisition of neural cell identity during in vitro differentiation of mouse embryonic stem cells. Dev Biol, 275, 124, 2004.
33.
LiY., GautamA., YangJ., QiuL., MelkoumianZ., WeberJ., TelukuntlaL., SrivastavaR., WhiteleyE.M., and BrandenbergerR.Differentiation of oligodendrocyte progenitor cells from human embryonic stem cells on vitronectin-derived synthetic peptide acrylate surface. Stem Cells Dev, 22, 1497, 2013.
34.
SartS., MaT., and LiY.Cryopreservation of pluripotent stem cell aggregates in defined protein-free formulation. Biotechnol Prog, 29, 143, 2013.
35.
LuH., HoshibaT., KawazoeN., and ChenG.Comparison of decellularization techniques for preparation of extracellular matrix scaffolds derived from three-dimensional cell culture. J Biomed Mater Res A, 100, 2507, 2012.
36.
GraysonW.L., MaT., and BunnellB.Human mesenchymal stem cells tissue development in 3D PET matrices. Biotechnol Prog, 20, 905, 2004.
37.
LiX., ChenY., ScheeleS., ArmanE., Haffner-KrauszR., EkblomP., and LonaiP.Fibroblast growth factor signaling and basement membrane assembly are connected during epithelial morphogenesis of the embryoid body. J Cell Biol, 153, 811, 2001.
38.
MatsuokaY., KubotaH., AdachiE., NagaiN., MarutaniT., HosokawaN., and NagataK.Insufficient folding of type IV collagen and formation of abnormal basement membrane-like structure in embryoid bodies derived from Hsp47-null embryonic stem cells. Mol Biol Cell, 15, 4467, 2004.
39.
GasimliL., StansfieldH.E., NairnA.V., LiuH., PaluhJ.L., YangB., DordickJ.S., MoremenK.W., and LinhardtR.J.Structural remodeling of proteoglycans upon retinoic acid-induced differentiation of NCCIT cells. Glycoconj J, 30, 497, 2013.
40.
BadylakS.F., FreytesD.O., and GilbertT.W.Extracellular matrix as a biological scaffold material: structure and function. Acta Biomater, 5, 1, 2009.
41.
BrafmanD.A., ShahK.D., FellnerT., ChienS., and WillertK.Defining long-term maintenance conditions of human embryonic stem cells with arrayed cellular microenvironment technology. Stem Cells Dev, 18, 1141, 2009.
42.
LeeS.T., YunJ.I., JoY.S., MochizukiM., van der VliesA.J., KontosS., IhmJ.E., LimJ.M., and HubbellJ.A.Engineering integrin signaling for promoting embryonic stem cell self-renewal in a precisely defined niche. Biomaterials, 31, 1219, 2010.
43.
SharowK.A., TemkinB., and Asson-BatresM.A.Retinoic acid stability in stem cell cultures. Int J Dev Biol, 56, 273, 2012.
44.
BelatikA., HotchandaniS., BariyangaJ., and Tajmir-RiahiH.A.Binding sites of retinol and retinoic acid with serum albumins. Eur J Med Chem, 48, 114, 2012.
45.
SimandiZ., BalintB.L., PoliskaS., RuhlR., and NagyL.Activation of retinoic acid receptor signaling coordinates lineage commitment of spontaneously differentiating mouse embryonic stem cells in embryoid bodies. FEBS Lett, 584, 3123, 2010.
46.
NedermanT., CarlssonJ., and MalmqvistM.Penetration of substances into tumor tissue—a methodological study on cellular spheroids. In Vitro, 17, 290, 1981.
47.
PersaudS.D., LinY.W., WuC.Y., KagechikaH., and WeiL.N.Cellular retinoic acid binding protein I mediates rapid non-canonical activation of ERK1/2 by all-trans retinoic acid. Cell Signal, 25, 19, 2012.
48.
KennedyK.A., PorterT., MehtaV., RyanS.D., PriceF., PeshdaryV., KaramboulasC., SavageJ., DrysdaleT.A., LiS.C., BennettS.A., and SkerjancI.S.Retinoic acid enhances skeletal muscle progenitor formation and bypasses inhibition by bone morphogenetic protein 4 but not dominant negative beta-catenin. BMC Biol, 7, 67, 2009.
CarpenedoR.L., Bratt-LealA.M., MarkleinR.A., SeamanS.A., BowenN.J., McDonaldJ.F., and McDevittT.C.Homogeneous and organized differentiation within embryoid bodies induced by microsphere-mediated delivery of small molecules. Biomaterials, 30, 2507, 2009.
51.
ChenN., and NapoliJ.L.All-trans-retinoic acid stimulates translation and induces spine formation in hippocampal neurons through a membrane-associated RARalpha. FASEB J, 22, 236, 2008.
52.
WieseC., RolletschekA., KaniaG., BlyszczukP., TarasovK.V., TarasovaY., WerstoR.P., BohelerK.R., and WobusA.M.Nestin expression—a property of multi-lineage progenitor cells?. Cell Mol Life Sci, 61, 2510, 2004.
53.
Bratt-LealA.M., CarpenedoR.L., UngrinM.D., ZandstraP.W., and McDevittT.C.Incorporation of biomaterials in multicellular aggregates modulates pluripotent stem cell differentiation. Biomaterials, 32, 48, 2011.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
