Engineering tissue morphogenesis: taking it up a Notch
2022; Elsevier BV; Volume: 40; Issue: 8 Linguagem: Inglês
10.1016/j.tibtech.2022.01.007
ISSN0167-9430
AutoresLaura A. Tiemeijer, Sami Şanlıdağ, Carlijn V. C. Bouten, Cecilia Sahlgren,
Tópico(s)Tissue Engineering and Regenerative Medicine
ResumoNotch signaling drives tissue patterning and morphogenesis during development and in the adult. Thus, targeting Notch can help to engineer tissues with defined form and function.Mimicking Notch-mediated patterning will require high spatiotemporal resolution for recapitulating in vivo patterning events.Targeting Notch signaling through materials functionalized with immobilized ligands is an engineering-friendly tool for controlling cell fate decisions with local precision and dose control.Important challenges remain in transforming the available concepts and tools into effective tissue-patterning strategies for regenerative medicine. Recreating functional tissues through bioengineering strategies requires steering of complex cell fate decisions. Notch, a juxtacrine signaling pathway, regulates cell fate and controls cellular organization with local precision. The engineering-friendly characteristics of the Notch pathway provide handles for engineering tissue patterning and morphogenesis. We discuss the physiological significance and mechanisms of Notch signaling with an emphasis on its potential use for engineering complex tissues. We highlight the current state of the art of Notch activation and provide a view on the design aspects, opportunities, and challenges in modulating Notch for tissue-engineering strategies. We propose that finely tuned control of Notch contributes to the generation of tissues with accurate form and functionality. Recreating functional tissues through bioengineering strategies requires steering of complex cell fate decisions. Notch, a juxtacrine signaling pathway, regulates cell fate and controls cellular organization with local precision. The engineering-friendly characteristics of the Notch pathway provide handles for engineering tissue patterning and morphogenesis. We discuss the physiological significance and mechanisms of Notch signaling with an emphasis on its potential use for engineering complex tissues. We highlight the current state of the art of Notch activation and provide a view on the design aspects, opportunities, and challenges in modulating Notch for tissue-engineering strategies. We propose that finely tuned control of Notch contributes to the generation of tissues with accurate form and functionality. Current bioengineered grafts generally provide living replacements for relatively simple tissues. However, they are not yet able to recreate complex tissue architectures and functionalities. Tissue architecture can be copied, for example by bioprinting, but recreating complex tissue function requires in-depth understanding of the developmental processes of their native counterparts as well as approaches to re-engineer and control these processes. Tissue development comprises spatiotemporal coordination of cells, and this coordination is crucial for the acquisition of cellular patterns during tissue development and regeneration [1.Briquez P.S. Hubbell J.A. Morphogenesis and tissue engineering.in: Lanza R. Principles of Tissue Engineering. 5th edn. Elsevier, 2020: 133-144Crossref Scopus (1) Google Scholar,2.Ventrella R. et al.Asymmetry at cell–cell interfaces direct cell sorting, boundary formation, and tissue morphogenesis.Exp. Cell Res. 2017; 358: 58-64Crossref PubMed Scopus (14) Google Scholar]. Therefore, facilitation of intercellular coordination via the delivery of spatially controlled signals is crucial for engineering patterning and morphogenesis. Juxtacrine cell signaling guides cell fate, patterning, and boundary formation through direct contacts between neighboring cells and offers handles to control cell signaling with local precision [2.Ventrella R. et al.Asymmetry at cell–cell interfaces direct cell sorting, boundary formation, and tissue morphogenesis.Exp. Cell Res. 2017; 358: 58-64Crossref PubMed Scopus (14) Google Scholar, 3.Nishida-Aoki N. Gujral T.S. Emerging approaches to study cell–cell interactions in tumor microenvironment.Oncotarget. 2019; 10: 785-797Crossref PubMed Google Scholar, 4.Fagotto F. Gumbiner B.M. Cell contact-dependent signaling.Dev. Biol. 1996; 180: 445-454Crossref PubMed Scopus (186) Google Scholar]. Notch is a conserved regulator of cell fate decisions, and the juxtacrine Notch signaling pathway orchestrates numerous fundamental morphogenic processes [5.Gazave E. et al.Origin and evolution of the Notch signalling pathway: an overview from eukaryotic genomes.BMC Evol. Biol. 2009; 9: 249Crossref PubMed Scopus (154) Google Scholar,6.Siebel C. Lendahl U. Notch signaling in development, tissue homeostasis, and disease.Physiol. Rev. 2017; 97: 1235-1294Crossref PubMed Scopus (410) Google Scholar]. Upon interactions between a Notch receptor presented on one cell and a ligand presented on another cell, the receptor releases an active intracellular fragment, which then moves to the nucleus where it regulates cell intrinsic developmental gene networks. Notch also controls multicellular patterning via lateral induction (see Glossary) and lateral inhibition. These signaling modes contribute to tissue organization by promoting uniform or differential cell fate decisions between adjacent cells, respectively [7.Sjöqvist M. Andersson E.R. Do as I say, Not(ch) as I do: lateral control of cell fate.Dev. Biol. 2019; 447: 58-70Crossref PubMed Scopus (51) Google Scholar] (see Figure I in Box 1). In this way, Notch dictates form and function during tissue morphogenesis (Figure 1).Box 1The Notch signaling pathwayNotch signaling is a contact-dependent pathway that is evolutionarily conserved in metazoans. In humans, Notch signaling is activated through the interactions of the Notch ligands Jagged (Jag) 1,2 and Delta-like ligands (Dll)-1,3,4 with Notch receptors (Notch1,2,3,4) that are present on the membranes of a ligand-presenting (sender) and a receptor-presenting (receiver) cell (Figure I). Each Notch receptor is a heterodimer of two subunits – a transmembrane/intracellular domain and a Notch extracellular domain (NECD). Upon receptor–ligand interaction, the sender cell internalizes the ligand together with the NECD [81.Hori K. et al.Notch signaling at a glance.J. Cell Sci. 2013; 126: 2135-2140Crossref PubMed Scopus (377) Google Scholar]. This creates a mechanical pull on the extracellular domain of the receptor to unfold the negative regulatory region (NRR) and reveal the S2 proteolytic cleavage site for a disintegrin and metalloprotease (ADAM) metalloproteinases. S2 cleavage is then followed by S3 cleavage mediated by γ-secretase that releases the active intracellular domain (NICD), which then translocates to the nucleus and interacts with CSL transcription factors to drive the transcription of Notch target genes [63.Kovall R.A. et al.The canonical Notch signaling pathway: structural and biochemical insights into shape, sugar, and force.Dev. Cell. 2017; 41: 228-241Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar]. Notch regulates important cell fate decisions such as migration, proliferation, differentiation, and apoptosis [6.Siebel C. Lendahl U. Notch signaling in development, tissue homeostasis, and disease.Physiol. Rev. 2017; 97: 1235-1294Crossref PubMed Scopus (410) Google Scholar]. In addition to controlling cell-intrinsic programs, the Notch signal can be processed in neighboring cells through positive and negative feedback loops that induce or repress ligand expression in the signal-receiving cell. These processes are called lateral induction and lateral inhibition, respectively. Which of these two processes becomes prominent is determined by the cellular context. Lateral induction promotes the same cell fate in the neighboring cells, whereas lateral inhibition leads to adoption of differential cell fates. These lateral events give rise to patterning of cell populations and contribute to their morphogenesis as functional compartments [7.Sjöqvist M. Andersson E.R. Do as I say, Not(ch) as I do: lateral control of cell fate.Dev. Biol. 2019; 447: 58-70Crossref PubMed Scopus (51) Google Scholar,81.Hori K. et al.Notch signaling at a glance.J. Cell Sci. 2013; 126: 2135-2140Crossref PubMed Scopus (377) Google Scholar]. Notch is involved in development from somitogenesis to postnatal stages, as well as in homeostasis, regeneration, and cancer in many adult tissues [6.Siebel C. Lendahl U. Notch signaling in development, tissue homeostasis, and disease.Physiol. Rev. 2017; 97: 1235-1294Crossref PubMed Scopus (410) Google Scholar].Figure 1Selected examples of Notch signaling in tissue patterning and morphogenesis.Show full captionNotch is involved in the tissue patterning and morphogenesis of multiple organs and tissues, both during development and in adult tissue patterning. Examples include (but are not restricted to) heart, skeletal muscle, vascular system, inner ear, intestine, pancreas, and liver.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Notch signaling is a contact-dependent pathway that is evolutionarily conserved in metazoans. In humans, Notch signaling is activated through the interactions of the Notch ligands Jagged (Jag) 1,2 and Delta-like ligands (Dll)-1,3,4 with Notch receptors (Notch1,2,3,4) that are present on the membranes of a ligand-presenting (sender) and a receptor-presenting (receiver) cell (Figure I). Each Notch receptor is a heterodimer of two subunits – a transmembrane/intracellular domain and a Notch extracellular domain (NECD). Upon receptor–ligand interaction, the sender cell internalizes the ligand together with the NECD [81.Hori K. et al.Notch signaling at a glance.J. Cell Sci. 2013; 126: 2135-2140Crossref PubMed Scopus (377) Google Scholar]. This creates a mechanical pull on the extracellular domain of the receptor to unfold the negative regulatory region (NRR) and reveal the S2 proteolytic cleavage site for a disintegrin and metalloprotease (ADAM) metalloproteinases. S2 cleavage is then followed by S3 cleavage mediated by γ-secretase that releases the active intracellular domain (NICD), which then translocates to the nucleus and interacts with CSL transcription factors to drive the transcription of Notch target genes [63.Kovall R.A. et al.The canonical Notch signaling pathway: structural and biochemical insights into shape, sugar, and force.Dev. Cell. 2017; 41: 228-241Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar]. Notch regulates important cell fate decisions such as migration, proliferation, differentiation, and apoptosis [6.Siebel C. Lendahl U. Notch signaling in development, tissue homeostasis, and disease.Physiol. Rev. 2017; 97: 1235-1294Crossref PubMed Scopus (410) Google Scholar]. In addition to controlling cell-intrinsic programs, the Notch signal can be processed in neighboring cells through positive and negative feedback loops that induce or repress ligand expression in the signal-receiving cell. These processes are called lateral induction and lateral inhibition, respectively. Which of these two processes becomes prominent is determined by the cellular context. Lateral induction promotes the same cell fate in the neighboring cells, whereas lateral inhibition leads to adoption of differential cell fates. These lateral events give rise to patterning of cell populations and contribute to their morphogenesis as functional compartments [7.Sjöqvist M. Andersson E.R. Do as I say, Not(ch) as I do: lateral control of cell fate.Dev. Biol. 2019; 447: 58-70Crossref PubMed Scopus (51) Google Scholar,81.Hori K. et al.Notch signaling at a glance.J. Cell Sci. 2013; 126: 2135-2140Crossref PubMed Scopus (377) Google Scholar]. Notch is involved in development from somitogenesis to postnatal stages, as well as in homeostasis, regeneration, and cancer in many adult tissues [6.Siebel C. Lendahl U. Notch signaling in development, tissue homeostasis, and disease.Physiol. Rev. 2017; 97: 1235-1294Crossref PubMed Scopus (410) Google Scholar]. Notch is involved in the tissue patterning and morphogenesis of multiple organs and tissues, both during development and in adult tissue patterning. Examples include (but are not restricted to) heart, skeletal muscle, vascular system, inner ear, intestine, pancreas, and liver. Owing to its engineering-friendly characteristics – as outlined in the following text – Notch emerges as a potent lever for controlling cell fate decisions and patterning in tissue engineering applications. Although Notch signaling has been used to control cell differentiation and expansion in vitro and in vivo (Table 1), attention has only recently been drawn to its use for guiding tissue patterning. This has been spurred by the development of engineering toolboxes and material design concepts (Figure 2, Key figure). In this review we discuss the role of Notch in tissue patterning and the rationale for targeting it for tissue engineering purposes. We provide an outlook on the current state of material-mediated bioengineering approaches for activating and fine-tuning Notch, as well as technical considerations and design challenges in its use for patterning tissues.Table 1Overview of studies of Notch ligand-functionalized (bio)materials and their respective target tissuesLigandCell/tissue typeRefsNotesDll1Muscle[41.Varnum-Finney B. et al.Immobilization of Notch ligand, Delta-1, is required for induction of notch signaling.J. Cell Sci. 2000; 113: 4313-4318Crossref PubMed Google Scholar,78.Safaee H. et al.Tethered Jagged-1 synergizes with culture substrate stiffness to modulate Notch-induced myogenic progenitor differentiation.Cell. Mol. Bioeng. 2017; 10: 501-513Crossref PubMed Scopus (12) Google Scholar]Immune/blood[24.Delaney C. et al.Dose-dependent effects of the Notch ligand Delta1 on ex vivo differentiation and in vivo marrow repopulating ability of cord blood cells.Blood. 2005; 106: 2693-2699Crossref PubMed Scopus (221) Google Scholar,27.Delaney C. et al.Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution.Nat. Med. 2010; 16: 232-236Crossref PubMed Scopus (596) Google Scholar,47.Lee J. Kotov N.A. Notch ligand presenting acellular 3D microenvironments for ex vivo human hematopoietic stem-cell culture made by layer-by-layer assembly.Small. 2009; 5: 1008-1013Crossref PubMed Scopus (61) Google Scholar,53.Winkler A.L. et al.Bioinstructive coatings for hematopoietic stem cell expansion based on chemical vapor deposition copolymerization.Biomacromolecules. 2017; 18: 3089-3098Crossref PubMed Scopus (6) Google Scholar,54.Winkler A.L. et al.Significance of nanopatterned and clustered DLL1 for hematopoietic stem cell proliferation.Adv. Funct. Mater. 2017; 27: 1606495Crossref Scopus (10) Google Scholar,69.Dallas M.H. et al.Density of the Notch ligand Delta1 determines generation of B and T cell precursors from hematopoietic stem cells.J. Exp. Med. 2005; 201: 1361-1366Crossref PubMed Scopus (100) Google Scholar,85.Kim H. et al.Notch ligand Delta-like 1 promotes in vivo vasculogenesis in human cord blood-derived endothelial colony forming cells.Cytotherapy. 2015; 17: 579-592Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar]Dental[42.Sukarawan W. et al.Effect of Jagged-1 and Dll-1 on osteogenic differentiation by stem cells from human exfoliated deciduous teeth.Arch. Oral Biol. 2016; 65: 1-8Crossref PubMed Scopus (20) Google Scholar]Cardiac/stem cells[37.Gerbin K.A. et al.Delta-1 functionalized hydrogel promotes hESC-cardiomyocyte graft proliferation and maintains heart function post-injury.Mol. Ther. Methods Clin. Dev. 2020; 17: 986-998Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar]−[55.Seo D. et al.A mechanogenetic toolkit for interrogating cell signaling in space and time.Cell. 2016; 165: 1507-1518Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar]Dll4Hepatic[70.Kaylan K.B. et al.Spatial patterning of liver progenitor cell differentiation mediated by cellular contractility and Notch signaling.Elife. 2018; 7e38536Crossref PubMed Scopus (12) Google Scholar]Reporter cells[86.Narui Y. Salaita K. Membrane tethered delta activates notch and reveals a role for spatio-mechanical regulation of the signaling pathway.Biophys. J. 2013; 105: 2655-2665Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar]Immune/blood[48.Shah N.J. et al.An injectable bone marrow-like scaffold enhances T cell immunity after hematopoietic stem cell transplantation.Nat. Biotechnol. 2019; 37: 293-302Crossref PubMed Scopus (62) Google Scholar,87.Taqvi S. et al.Biomaterial-based notch signaling for the differentiation of hematopoietic stem cells into T cells.J. Biomed. Mater. Res. A. 2006; 79: 689-697Crossref PubMed Scopus (58) Google Scholar]Cancer/HeLa cells[68.Liu L. et al.Identification of domains for efficient Notch signaling activity in immobilized Notch ligand proteins.J. Cell. Biochem. 2016; 118: 785-796Crossref PubMed Scopus (10) Google Scholar]Endothelial[30.Tiemeijer L.A. et al.Spatial patterning of the Notch ligand Dll4 controls endothelial sprouting in vitro.Sci. Rep. 2018; 8: 6392Crossref PubMed Scopus (14) Google Scholar]DeltaaLigand number was not specified in this study.Reporter cells[56.Deforest C.A. Tirrell D.A. A photoreversible protein-patterning approach for guiding stem cell fate in three-dimensional gels.Nat. Mater. 2015; 14: 523-531Crossref PubMed Scopus (321) Google Scholar]Jag1Immune/blood[43.Toda H. et al.Orientation-regulated immobilization of Jagged1 on glass substrates for ex vivo proliferation of a bone marrow cell population containing hematopoietic stem cells.Biomaterials. 2011; 32: 6920-6928Crossref PubMed Scopus (21) Google Scholar,46.Gonçalves R.M. et al.Induction of notch signaling by immobilization of jagged-1 on self-assembled monolayers.Biomaterials. 2009; 30: 6879-6887Crossref PubMed Scopus (27) Google Scholar]Epithelial[44.Beckstead B.L. et al.Mimicking cell–cell interactions at the biomaterial–cell interface for control of stem cell differentiation.J. Biomed. Mater. Res. A. 2006; 79: 94-103Crossref PubMed Scopus (84) Google Scholar], [45.Beckstead B.L. et al.Methods to promote Notch signaling at the biomaterial interface and evaluation in a rafted organ culture model.J. Biomed. Mater. Res. A. 2009; 91: 436-446Crossref PubMed Scopus (33) Google Scholar]b,Peptide was included in the study. [66.Matea C.T. et al.Rational design of gold nanocarrier for the delivery of JAG-1 peptide.J. Nanobiotechnol. 2015; 13: 41Crossref PubMed Scopus (4) Google Scholar]b,Peptide was included in the study. [88.Nickoloff B.J. et al.Jagged-1 mediated activation of notch signaling induces complete maturation of human keratinocytes through NF-κB and PPARγ.Cell Death Differ. 2002; 9: 842-855Crossref PubMed Scopus (267) Google Scholar]bPeptide was included in the study.PeptidebPeptide was included in the study.Dental[25.Osathanon T. et al.Surface-bound orientated Jagged-1 enhances osteogenic differentiation of human periodontal ligament-derived mesenchymal stem cells.J. Biomed. Mater. Res. A. 2013; 101: 358-367Crossref PubMed Scopus (58) Google Scholar,42.Sukarawan W. et al.Effect of Jagged-1 and Dll-1 on osteogenic differentiation by stem cells from human exfoliated deciduous teeth.Arch. Oral Biol. 2016; 65: 1-8Crossref PubMed Scopus (20) Google Scholar,89.Osathanon T. et al.BFGF and JAGGED1 regulate alkaline phosphatase expression and mineralization in dental tissue-derived mesenchymal stem cells.J. Cell. Biochem. 2013; 114: 2551-2561Crossref PubMed Scopus (40) Google Scholar, 90.Manokawinchoke J. et al.Indirect immobilized Jagged1 suppresses cell cycle progression and induces odonto/osteogenic differentiation in human dental pulp cells.Sci. Rep. 2017; 7: 10124Crossref PubMed Scopus (24) Google Scholar, 91.Nowwarote N. et al.Characterization of a bioactive Jagged1-coated polycaprolactone-based membrane for guided tissue regeneration.Arch. Oral Biol. 2018; 88: 24-33Crossref PubMed Scopus (11) Google Scholar]Muscle[78.Safaee H. et al.Tethered Jagged-1 synergizes with culture substrate stiffness to modulate Notch-induced myogenic progenitor differentiation.Cell. Mol. Bioeng. 2017; 10: 501-513Crossref PubMed Scopus (12) Google Scholar]Cardiac[40.Tung J.C. et al.Engineered biomaterials control differentiation and proliferation of human-embryonic-stem-cell-derived cardiomyocytes via timed notch activation.Stem Cell Rep. 2014; 2: 271-281Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar]bPeptide was included in the study., [51.Wen F. et al.Induction of myogenic differentiation of human mesenchymal stem cells cultured on notch agonist (jagged-1) modified biodegradable scaffold surface.ACS Appl. Mater. Interfaces. 2014; 6: 1652-1661Crossref PubMed Scopus (21) Google Scholar]bPeptide was included in the study.Reporter cells, stem cells[49.Ndong J.D.L.C. et al.Controlled JAGGED1 delivery induces human embryonic palate mesenchymal cells to form osteoblasts.J. Biomed. Mater. Res. A. 2018; 106: 552-560Crossref PubMed Scopus (9) Google Scholar], [52.Boopathy A.V. et al.The modulation of cardiac progenitor cell function by hydrogel-dependent Notch1 activation.Biomaterials. 2014; 35: 8103-8112Crossref PubMed Scopus (42) Google Scholar]b,Peptide was included in the study. [67.Putti M. et al.Influence of the assembly state on the functionality of a supramolecular jagged1-mimicking peptide additive.ACS Omega. 2019; 4: 8178-8187Crossref PubMed Scopus (8) Google Scholar]b,Peptide was included in the study. [72.Putti M. et al.A supramolecular platform for the introduction of Fc-fusion bioactive proteins on biomaterial surfaces.ACS Appl. Polym. Mater. 2019; 1: 2044-2054Crossref PubMed Scopus (6) Google Scholar]bPeptide was included in the study.PeptidebPeptide was included in the study.Bone[71.Dishowitz M.I. et al.Jagged1 immobilization to an osteoconductive polymer activates the Notch signaling pathway and induces osteogenesis.J. Biomed. Mater. Res. A. 2014; 102: 1558-1567Crossref PubMed Scopus (43) Google Scholar]Hepatic[57.Rizwan M. et al.Photochemically activated Notch signaling hydrogel preferentially differentiates human derived hepatoblasts to cholangiocytes.Adv. Funct. Mater. 2021; 31: 2006116Crossref Scopus (4) Google Scholar]a Ligand number was not specified in this study.b Peptide was included in the study. Open table in a new tab The Notch pathway regulates developmental genetic programs, and there is extensive crosstalk between the Notch pathway and many other signaling pathways involved in organ development [8.Collu G.M. et al.Wnt–Notch signalling crosstalk in development and disease.Cell. Mol. Life Sci. 2014; 71: 3553-3567Crossref PubMed Scopus (125) Google Scholar, 9.Jacobs C.T. Huang P. Complex crosstalk of Notch and Hedgehog signalling during the development of the central nervous system.Cell. Mol. Life Sci. 2021; 78: 635-644Crossref PubMed Scopus (3) Google Scholar, 10.Munnamalai V. Fekete D.M. Notch–Wnt–Bmp crosstalk regulates radial patterning in the mouse cochlea in a spatiotemporal manner.Development. 2016; 143: 4003-4015Crossref PubMed Scopus (43) Google Scholar]. Notch thus acts as a gatekeeper for the molecular cascades that lead to important cell fate decisions during tissue morphogenesis [6.Siebel C. Lendahl U. Notch signaling in development, tissue homeostasis, and disease.Physiol. Rev. 2017; 97: 1235-1294Crossref PubMed Scopus (410) Google Scholar,11.MacGrogan D. et al.Notch and interacting signalling pathways in cardiac development, disease, and regeneration.Nat. Rev. Cardiol. 2018; 15: 685-704Crossref PubMed Scopus (87) Google Scholar, 12.Bi P. et al.Stage-specific effects of Notch activation during skeletal myogenesis.Elife. 2016; 5e17355Crossref Scopus (44) Google Scholar, 13.Sancho R. et al.Stem cell and progenitor fate in the mammalian intestine: Notch and lateral inhibition in homeostasis and disease.EMBO Rep. 2015; 16: 571-581Crossref PubMed Scopus (103) Google Scholar]. Examples include the formation of heart valves, bile ducts in the liver, and pancreatic tissues, the regeneration of intestinal crypts and skeletal muscle, and tissue vascularization (Figure 1) [6.Siebel C. Lendahl U. Notch signaling in development, tissue homeostasis, and disease.Physiol. Rev. 2017; 97: 1235-1294Crossref PubMed Scopus (410) Google Scholar,11.MacGrogan D. et al.Notch and interacting signalling pathways in cardiac development, disease, and regeneration.Nat. Rev. Cardiol. 2018; 15: 685-704Crossref PubMed Scopus (87) Google Scholar,13.Sancho R. et al.Stem cell and progenitor fate in the mammalian intestine: Notch and lateral inhibition in homeostasis and disease.EMBO Rep. 2015; 16: 571-581Crossref PubMed Scopus (103) Google Scholar, 14.Afelik S. Jensen J. Notch signaling in the pancreas: patterning and cell fate specification.Wiley Interdiscip. Rev. Dev. Biol. 2013; 2: 531-544Crossref PubMed Scopus (44) Google Scholar, 15.Sueda R. Kageyama R. Regulation of active and quiescent somatic stem cells by Notch signaling.Develop. Growth Differ. 2020; 62: 59-66Crossref PubMed Scopus (36) Google Scholar, 16.Adams J.M. Jafar-Nejad H. The roles of notch signaling in liver development and disease.Biomolecules. 2019; 9: 608Crossref Scopus (30) Google Scholar]. Modulation of Notch thus allows control over cell fate in engineered environments. Notch can guide tissue patterning in multiple tissue-engineering contexts and aid in culturing organ and tissue mimics for biomedical research in the laboratory (Figure 2, first tier). Although the role of Notch signaling in various biological processes has previously been the subject of excellent reviews [6.Siebel C. Lendahl U. Notch signaling in development, tissue homeostasis, and disease.Physiol. Rev. 2017; 97: 1235-1294Crossref PubMed Scopus (410) Google Scholar,7.Sjöqvist M. Andersson E.R. Do as I say, Not(ch) as I do: lateral control of cell fate.Dev. Biol. 2019; 447: 58-70Crossref PubMed Scopus (51) Google Scholar], in this section we highlight some examples, focusing on the potential of Notch for tissue patterning in the context of tissue engineering. Notch guides cell-intrinsic processes that are important for morphogenesis, such as proliferation, migration, and differentiation, and also defines tissue fields and boundaries via lateral patterning mechanisms. Notch is involved in cell fate decisions that give rise to functional compartments in the developing heart. During the morphogenesis of valves, Notch mediates the epithelial-to-mesenchymal transition predominantly through delta-like ligand (Dll) 4 activity to promote the formation of the endocardial cushions. Later, endocardial Jagged 1 (Jag1) mediates cushion fusion by restricting mesenchymal proliferation [17.MacGrogan D. et al.Sequential ligand-dependent Notch signaling activation regulates valve primordium formation and morphogenesis.Circ. Res. 2016; 118: 1480-1497Crossref PubMed Scopus (59) Google Scholar]. During ventricular development, endocardial Dll4 activity in the trabecular base and subsequent myocardial Jag1/2 activity control trabeculae formation and myocardial compaction, respectively [18.D'Amato G. et al.Sequential Notch activation regulates ventricular chamber development.Nat. Cell Biol. 2016; 18: 7-20Crossref PubMed Scopus (108) Google Scholar]. The same ligands guide the formation of coronary vessels throughout the compacting myocardium [19.Travisano S.I. et al.Coronary arterial development is regulated by a Dll4-jag1–ephrinb2 signaling cascade.Elife. 2019; 8e49977Crossref PubMed Scopus (13) Google Scholar]. In some tissues, lateral patterning events are prominent, and they significantly guide tissue shape and function. For example, during aortic arch development, Jag1 promotes the differentiation of vascular smooth muscle cells (VSMCs) from progenitors through lateral induction [20.Manderfield L.J. et al.Notch activation of Jagged1 contributes to the assembly of the arterial wall.Circulation. 2012; 125: 314-323Crossref PubMed Scopus (113) Google Scholar]. In the developing pancreas, Dll1-mediated lateral inhibition regulates progenitor maintenance and differentiation as well as pancreatic epithelium branching via tip versus trunk cell selection [14.Afelik S. Jensen J. Notch signaling in the pancreas: patterning and cell fate specification.Wiley Interdiscip. Rev. Dev. Biol. 2013; 2: 531-544Crossref PubMed Scopus (44) Google Scholar]. During inner-ear development, the organ of Corti is patterned through consecutive lateral induction and inhibition events mediated by Jag1/2 and Dll1, which draw the tissue boundaries and also direct sensory hair versus supporting cell differentiation [7.Sjöqvist M. Andersson E.R. Do as I say, Not(ch) as I do: lateral control of cell fate.Dev. Biol. 2019; 447: 58-70Crossref PubMed Scopus (51) Google Scholar,21.Basch M.L. et al.Fine-tuning of Notch signaling sets the boundary of the organ of Corti and establishes sensory cell fates.Elife. 2016; 5e19921Crossref PubMed Scopus (41) Google Scholar]. All in all, Notch controls important cell fate decisions which are important for gain of form and function during development, and can also mediate morphogenesis across tissue planes through lateral patterning events. Thus, controlling Notch may offer a handle to control morphogenesis in a wide range of tissues and organs. The role of Notch in tissue patterning during development also often translates to their regeneration in adults. Notch contributes to the regeneration and homeostasis of many tissues and organs including skeletal muscle, vascular wall, heart, liver, and intestines in the adult, for example by regulating the balance between the stem cell pool and the differentiated cells, as well as regulating multiple differentiation events and cellular organization [11.MacGrogan D. et al.Notch and interacting signalling pat
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