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1
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Khandan V, Chiechi RC, Verpoorte E, Mathwig K. Suppressing parasitic flow in membraneless diffusion-based microfluidic gradient generators. LAB ON A CHIP 2025; 25:1875-1887. [PMID: 40052553 DOI: 10.1039/d4lc00956h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/26/2025]
Abstract
Diffusion-based microfluidic gradient generators (DMGGs) are essential for various in vitro studies due to their ability to provide a convection-free concentration gradient. However, these systems, often referred to as membrane-based DMGGs, exhibit delayed gradient formation due to the incorporated flow-resistant membrane. This limitation substantially hinders their application in dynamic and time-sensitive studies. Here, we accelerate the gradient response in DMGGs by removing the membrane and implementing new geometrical configurations to compensate for the membrane's role in suppressing parasitic flows. We introduce these novel configurations into two microfluidic designs: the H-junction and the Y-junction. In the H-junction design, parasitic flow is redirected through a bypass channel following the gradient region. The Y-junction design features a shared discharge channel that allows converging discharge flow streams, preventing the buildup of parasitic pressure downstream of the gradient region. Using hydraulic circuit analysis and fluid dynamics simulations, we demonstrate the effectiveness of the H-junction and Y-junction designs in suppressing parasitic pressure flows. These computational results, supported by experimental data from particle image velocimetry, confirm the capability of our designs to generate a highly stable, accurate, and convection-free gradient with rapid formation. These advantages make the H-junction and Y-junction designs ideal experimental platforms for a wide range of in vitro studies, including drug testing, cell chemotaxis, and stem cell differentiation.
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Affiliation(s)
- Vahid Khandan
- University of Groningen, Groningen Research Institute of Pharmacy, Pharmaceutical Analysis, 9700 AD Groningen, The Netherlands
| | - Ryan C Chiechi
- Stratingh Institute for Chemistry and Zernike Institute for Advanced Materials, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
- Department of Chemistry & Organic and Carbon Electronics Laboratory, North Carolina State University, Raleigh, NC, 27695, USA
| | - Elisabeth Verpoorte
- University of Groningen, Groningen Research Institute of Pharmacy, Pharmaceutical Analysis, 9700 AD Groningen, The Netherlands
| | - Klaus Mathwig
- University of Groningen, Groningen Research Institute of Pharmacy, Pharmaceutical Analysis, 9700 AD Groningen, The Netherlands
- imec within OnePlanet Research Center, Bronland 10, 6708 WH Wageningen, The Netherlands.
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2
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Sharma B, Agriantonis G, Twelker K, Ebelle D, Kiernan S, Siddiqui M, Soni A, Cheerasarn S, Simon W, Jiang W, Cardona A, Chapelet J, Agathis AZ, Gamboa A, Dave J, Mestre J, Bhatia ND, Shaefee Z, Whittington J. Gut Microbiota Serves as a Crucial Independent Biomarker in Inflammatory Bowel Disease (IBD). Int J Mol Sci 2025; 26:2503. [PMID: 40141145 PMCID: PMC11942158 DOI: 10.3390/ijms26062503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Revised: 03/03/2025] [Accepted: 03/06/2025] [Indexed: 03/28/2025] Open
Abstract
Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD), ulcerative colitis (UC), and IBD unclassified (IBD-U), is a complex intestinal disorder influenced by genetic, environmental, and microbial factors. Recent evidence highlights the gut microbiota as a pivotal biomarker and modulator in IBD pathogenesis. Dysbiosis, characterized by reduced microbial diversity and altered composition, is a hallmark of IBD. A consistent decrease in anti-inflammatory bacteria, such as Faecalibacterium prausnitzii, and an increase in pro-inflammatory species, including Escherichia coli, have been observed. Metabolomic studies reveal decreased short-chain fatty acids (SCFAs) and secondary bile acids, critical for gut homeostasis, alongside elevated pro-inflammatory metabolites. The gut microbiota interacts with host immune pathways, influencing morphogens, glycosylation, and podoplanin (PDPN) expression. The disruption of glycosylation impairs mucosal barriers, while aberrant PDPN activity exacerbates inflammation. Additionally, microbial alterations contribute to oxidative stress, further destabilizing intestinal barriers. These molecular and cellular disruptions underscore the role of the microbiome in IBD pathophysiology. Emerging therapeutic strategies, including probiotics, prebiotics, and dietary interventions, aim to restore microbial balance and mitigate inflammation. Advanced studies on microbiota-targeted therapies reveal their potential to reduce disease severity and improve patient outcomes. Nevertheless, further research is needed to elucidate the bidirectional interactions between the gut microbiome and host immune responses and to translate these insights into clinical applications. This review consolidates current findings on the gut microbiota's role in IBD, emphasizing its diagnostic and therapeutic implications, and advocates for the continued exploration of microbiome-based interventions to combat this debilitating disease.
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Affiliation(s)
- Bharti Sharma
- Department of Surgery, NYC Health and Hospitals—Elmhurst, New York, NY 11373, USA; (B.S.); (G.A.); (S.K.); (S.C.); (A.C.); (J.D.); (J.M.); (N.D.B.); (Z.S.)
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (W.J.); (A.Z.A.)
| | - George Agriantonis
- Department of Surgery, NYC Health and Hospitals—Elmhurst, New York, NY 11373, USA; (B.S.); (G.A.); (S.K.); (S.C.); (A.C.); (J.D.); (J.M.); (N.D.B.); (Z.S.)
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (W.J.); (A.Z.A.)
| | - Kate Twelker
- Department of Surgery, NYC Health and Hospitals—Elmhurst, New York, NY 11373, USA; (B.S.); (G.A.); (S.K.); (S.C.); (A.C.); (J.D.); (J.M.); (N.D.B.); (Z.S.)
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (W.J.); (A.Z.A.)
| | - Danielle Ebelle
- Department of Medicine, St. George’s University, Grenada FZ818, West Indies; (D.E.); (M.S.); (W.S.); (J.C.)
| | - Samantha Kiernan
- Department of Surgery, NYC Health and Hospitals—Elmhurst, New York, NY 11373, USA; (B.S.); (G.A.); (S.K.); (S.C.); (A.C.); (J.D.); (J.M.); (N.D.B.); (Z.S.)
| | - Maham Siddiqui
- Department of Medicine, St. George’s University, Grenada FZ818, West Indies; (D.E.); (M.S.); (W.S.); (J.C.)
| | - Aditi Soni
- Department of Medicine, St. George’s University, Grenada FZ818, West Indies; (D.E.); (M.S.); (W.S.); (J.C.)
| | - Sittha Cheerasarn
- Department of Surgery, NYC Health and Hospitals—Elmhurst, New York, NY 11373, USA; (B.S.); (G.A.); (S.K.); (S.C.); (A.C.); (J.D.); (J.M.); (N.D.B.); (Z.S.)
| | - Whenzdjyny Simon
- Department of Medicine, St. George’s University, Grenada FZ818, West Indies; (D.E.); (M.S.); (W.S.); (J.C.)
| | - Winston Jiang
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (W.J.); (A.Z.A.)
| | - Angie Cardona
- Department of Surgery, NYC Health and Hospitals—Elmhurst, New York, NY 11373, USA; (B.S.); (G.A.); (S.K.); (S.C.); (A.C.); (J.D.); (J.M.); (N.D.B.); (Z.S.)
| | - Jessica Chapelet
- Department of Medicine, St. George’s University, Grenada FZ818, West Indies; (D.E.); (M.S.); (W.S.); (J.C.)
| | - Alexandra Z. Agathis
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (W.J.); (A.Z.A.)
| | - Alejandro Gamboa
- Department of Medicine, Medical University of the Americas, Devens, MA 01434, USA;
| | - Jasmine Dave
- Department of Surgery, NYC Health and Hospitals—Elmhurst, New York, NY 11373, USA; (B.S.); (G.A.); (S.K.); (S.C.); (A.C.); (J.D.); (J.M.); (N.D.B.); (Z.S.)
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (W.J.); (A.Z.A.)
| | - Juan Mestre
- Department of Surgery, NYC Health and Hospitals—Elmhurst, New York, NY 11373, USA; (B.S.); (G.A.); (S.K.); (S.C.); (A.C.); (J.D.); (J.M.); (N.D.B.); (Z.S.)
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (W.J.); (A.Z.A.)
| | - Navin D. Bhatia
- Department of Surgery, NYC Health and Hospitals—Elmhurst, New York, NY 11373, USA; (B.S.); (G.A.); (S.K.); (S.C.); (A.C.); (J.D.); (J.M.); (N.D.B.); (Z.S.)
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (W.J.); (A.Z.A.)
| | - Zahra Shaefee
- Department of Surgery, NYC Health and Hospitals—Elmhurst, New York, NY 11373, USA; (B.S.); (G.A.); (S.K.); (S.C.); (A.C.); (J.D.); (J.M.); (N.D.B.); (Z.S.)
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (W.J.); (A.Z.A.)
| | - Jennifer Whittington
- Department of Surgery, NYC Health and Hospitals—Elmhurst, New York, NY 11373, USA; (B.S.); (G.A.); (S.K.); (S.C.); (A.C.); (J.D.); (J.M.); (N.D.B.); (Z.S.)
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (W.J.); (A.Z.A.)
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3
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Avdeeva M, Chalifoux M, Joyce B, Shvartsman SY, Posfai E. Generative model for the first cell fate bifurcation in mammalian development. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.24.639895. [PMID: 40060535 PMCID: PMC11888292 DOI: 10.1101/2025.02.24.639895] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/20/2025]
Abstract
The first cell fate bifurcation in mammalian development directs cells toward either the trophectoderm (TE) or inner cell mass (ICM) compartments in preimplantation embryos. This decision is regulated by the subcellular localization of a transcriptional co-activator YAP and takes place over several progressively asynchronous cleavage divisions. As a result of this asynchrony and variable arrangement of blastomeres, reconstructing the dynamics of the TE/ICM cell specification from fixed embryos is extremely challenging. To address this, we developed a live imaging approach and applied it to measure pairwise dynamics of nuclear YAP and its direct target genes, CDX2 and SOX2, key transcription factors of TE and ICM, respectively. Using these datasets, we constructed a generative model of the first cell fate bifurcation, which reveals the time-dependent statistics of the TE and ICM cell allocation. In addition to making testable predictions for the joint dynamics of the full YAP/CDX2/SOX2 motif, the model revealed the stochastic nature of the induction timing of the key cell fate determinants and identified the features of YAP dynamics that are necessary or sufficient for this induction. Notably, temporal heterogeneity was particularly prominent for SOX2 expression among ICM cells. As heterogeneities within the ICM have been linked to the initiation of the second cell fate decision in the embryo, understanding the origins of this variability is of key significance. The presented approach reveals the dynamics of the first cell fate choice and lays the groundwork for dissecting the next cell fate bifurcations in mouse development.
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Affiliation(s)
- Maria Avdeeva
- Center for Computational Biology, Flatiron Institute, Simons Foundation, New York, New York, USA
| | - Madeleine Chalifoux
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, USA
- Department of Molecular Biology, Princeton, New Jersey, USA
| | - Bradley Joyce
- Department of Molecular Biology, Princeton, New Jersey, USA
| | - Stanislav Y Shvartsman
- Center for Computational Biology, Flatiron Institute, Simons Foundation, New York, New York, USA
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, USA
- Department of Molecular Biology, Princeton, New Jersey, USA
| | - Eszter Posfai
- Department of Molecular Biology, Princeton, New Jersey, USA
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4
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Galliot B, Wenger Y. Organizer formation, organizer maintenance and epithelial cell plasticity in Hydra: Role of the Wnt3/β-catenin/TCF/Sp5/Zic4 gene network. Cells Dev 2025:204002. [PMID: 39929422 DOI: 10.1016/j.cdev.2025.204002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Accepted: 02/06/2025] [Indexed: 02/14/2025]
Abstract
The experimental and conceptual knowledge in 1909 led to the discovery of the Hydra head organizer through transplantation experiments between pigmented and non-pigmented animals; a discovery followed by numerous transplantations demonstrating cross-regulation between activating and inhibiting components distributed along the body axis. This experimental work inspired mathematicians, engineers, physicists and computer scientists to develop theoretical models predicting the principles of developmental mechanisms. Today, we know that the Wnt/β-catenin/Sp5/Zic4 gene regulatory network (GRN) links organizer activity, morphogenesis and cellular identity in Hydra, with variable conformations depending on the region or epithelial layer, and varied phenotypes depending on which GRN element is misregulated. In intact animals, Wnt/β-catenin signaling acts as the head activator at the tip of the hypostome, restricted by Sp5 in the other regions of the animal. Moreover, in the tentacle ring, Sp5 and Zic4 act epistatically to support tentacle differentiation and prevent basal disc differentiation. Along the body column, Sp5 is self-repressed in the epidermis and acts as a head inhibitor along the gastrodermis. Other players modulate these activities, such as TSP and Margin/RAX apically, Notch signaling in the tentacle zone, Dkk1/2/4 and HAS-7 in the body column. In the developmental context of regeneration, cells below the amputation zone switch from repressed to locally de novo activated head organizer status, a transition driven by immediate symmetrical and asymmetrical metabolic changes that lead to gene expression regulations involving components and modulators of Wnt/β-catenin signaling, early-pulse and early-late transient both often symmetrical, together with sustained ones, specific to head regeneration.
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Affiliation(s)
- Brigitte Galliot
- Department of Genetics and Evolution, University of Geneva, Geneva, Switzerland.
| | - Yvan Wenger
- Department of Genetics and Evolution, University of Geneva, Geneva, Switzerland
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5
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Chideriotis S, Anastasiadi AT, Tzounakas VL, Fortis SP, Kriebardis AG, Valsami S. Morphogens and Cell-Derived Structures (Exosomes and Cytonemes) as Components of the Communication Between Cells. Int J Mol Sci 2025; 26:881. [PMID: 39940651 PMCID: PMC11816454 DOI: 10.3390/ijms26030881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 01/16/2025] [Accepted: 01/18/2025] [Indexed: 02/16/2025] Open
Abstract
Morphogens, which are non-classical transcription factors, according to several studies, display a crucial role in tissue patterning, organ architecture establishment, and human disease pathogenesis. Recent advances have expanded the morphogen participation to a wide range of human diseases. There are many genetic syndromes caused by mutations of components of morphogen signaling pathways. The aberrant morphogen pathways also promote cancer cell maintenance, renewal, proliferation, and migration. On the other hand, exosomes and their application in the biomedical field are of evolving significance. The evidence that membrane structures participate in the creation of morphogenic gradience and biodistribution of morphogen components renders them attractive as new therapeutic tools. This intercellular morphogen transport is performed by cell-derived structures, mainly exosomes and cytonemes, and extracellular substances like heparan sulphate proteoglycans and lipoproteins. The interaction between morphogens and Extracellular Vesicles has been observed at first in the most studied insect, Drosophila, and afterwards analogous findings have been proved in vertebrates. This review presents the protagonists and mechanisms of lipid-modified morphogens (Hedgehog and Wnt/β-catenin) biodistribution.
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Affiliation(s)
| | - Alkmini T. Anastasiadi
- Department of Biochemistry, School of Medicine, University of Patras, 26504 Patras, Greece; (A.T.A.); (V.L.T.)
| | - Vassilis L. Tzounakas
- Department of Biochemistry, School of Medicine, University of Patras, 26504 Patras, Greece; (A.T.A.); (V.L.T.)
| | - Sotirios P. Fortis
- Laboratory of Reliability and Quality Control in Laboratory Hematology (HemQcR), Department of Biomedical Sciences, School of Health & Caring Sciences, University of West Attica (UniWA), 12243 Egaleo, Greece; (S.P.F.); (A.G.K.)
| | - Anastasios G. Kriebardis
- Laboratory of Reliability and Quality Control in Laboratory Hematology (HemQcR), Department of Biomedical Sciences, School of Health & Caring Sciences, University of West Attica (UniWA), 12243 Egaleo, Greece; (S.P.F.); (A.G.K.)
| | - Serena Valsami
- Hematology Laboratory, Blood Bank, Aretaieion Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece
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6
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Santorelli M, Bhamidipati PS, Courte J, Swedlund B, Jain N, Poon K, Schildknecht D, Kavanagh A, MacKrell VA, Sondkar T, Malaguti M, Quadrato G, Lowell S, Thomson M, Morsut L. Control of spatio-temporal patterning via cell growth in a multicellular synthetic gene circuit. Nat Commun 2024; 15:9867. [PMID: 39562554 DOI: 10.1038/s41467-024-53078-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 10/01/2024] [Indexed: 11/21/2024] Open
Abstract
A major goal in synthetic development is to build gene regulatory circuits that control patterning. In natural development, an interplay between mechanical and chemical communication shapes the dynamics of multicellular gene regulatory circuits. For synthetic circuits, how non-genetic properties of the growth environment impact circuit behavior remains poorly explored. Here, we first describe an occurrence of mechano-chemical coupling in synthetic Notch (synNotch) patterning circuits: high cell density decreases synNotch-gated gene expression in different cellular systems in vitro. We then construct, both in vitro and in silico, a synNotch-based signal propagation circuit whose outcome can be regulated by cell density. Spatial and temporal patterning outcomes of this circuit can be predicted and controlled via modulation of cell proliferation, initial cell density, and/or spatial distribution of cell density. Our work demonstrates that synthetic patterning circuit outcome can be controlled via cellular growth, providing a means for programming multicellular circuit patterning outcomes.
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Affiliation(s)
- Marco Santorelli
- Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Pranav S Bhamidipati
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
- Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Josquin Courte
- Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Benjamin Swedlund
- Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Naisargee Jain
- Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Kyle Poon
- Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Dominik Schildknecht
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Andriu Kavanagh
- Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Department of Biology, California State University Northridge, Northridge, CA, USA
| | - Victoria A MacKrell
- Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Trusha Sondkar
- Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Mattias Malaguti
- Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh, UK
- Centre for Engineering Biology, Institute of Quantitative Biology, Biochemistry and Biotechnology, School of Biological Sciences, The University of Edinburgh, Edinburgh, UK
| | - Giorgia Quadrato
- Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Sally Lowell
- Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh, UK
| | - Matt Thomson
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
- Department of Computing and Mathematical Sciences, California Institute of Technology, Pasadena, CA, USA.
- Beckman Center for Single-Cell Profiling and Engineering, Pasadena, CA, USA.
| | - Leonardo Morsut
- Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
- Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, USA.
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7
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Ell CM, Safyan A, Chayengia M, Kustermann MMM, Lorenz J, Schächtle M, Pyrowolakis G. A genome-engineered tool set for Drosophila TGF-β/BMP signaling studies. Development 2024; 151:dev204222. [PMID: 39494616 DOI: 10.1242/dev.204222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 10/15/2024] [Indexed: 11/05/2024]
Abstract
Ligands of the TGF-β/BMP superfamily are crucially involved in the regulation of growth, patterning and organogenesis and can act as long-range morphogens. Essential for understanding TGF-β/BMP signaling dynamics and regulation are tools that allow monitoring and manipulating pathway components at physiological expression levels and endogenous spatiotemporal patterns. We used genome engineering to generate a comprehensive library of endogenously epitope- or fluorescent-tagged versions of receptors, co-receptors, transcription factors and key feedback regulators of the Drosophila BMP and Activin signaling pathways. We demonstrate that the generated alleles are biologically active and can be used for assessing tissue and subcellular distribution of the corresponding proteins. Furthermore, we show that the genomic platforms can be used for in locus structure-function and cis-regulatory analyses. Finally, we present a complementary set of protein binder-based tools, which allow visualization as well as manipulation of the stability and subcellular localization of epitope-tagged proteins, providing new tools for the analysis of BMP signaling and beyond.
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Affiliation(s)
- Clara-Maria Ell
- Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, 79104 Freiburg, Germany
- CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany
- Institute for Biology I, Faculty of Biology, HMH, Habsburgerstr. 49, University of Freiburg, 79104 Freiburg, Germany
| | - Abu Safyan
- CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany
- Institute for Biology I, Faculty of Biology, HMH, Habsburgerstr. 49, University of Freiburg, 79104 Freiburg, Germany
- International Max Planck Research School for Immunobiology, Epigenetics, and Metabolism, 79108 Freiburg, Germany
| | - Mrinal Chayengia
- Institute for Biology I, Faculty of Biology, HMH, Habsburgerstr. 49, University of Freiburg, 79104 Freiburg, Germany
| | - Manuela M M Kustermann
- Institute for Biology I, Faculty of Biology, HMH, Habsburgerstr. 49, University of Freiburg, 79104 Freiburg, Germany
| | - Jennifer Lorenz
- Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, 79104 Freiburg, Germany
- Institute for Biology I, Faculty of Biology, HMH, Habsburgerstr. 49, University of Freiburg, 79104 Freiburg, Germany
| | - Melanie Schächtle
- Institute for Biology I, Faculty of Biology, HMH, Habsburgerstr. 49, University of Freiburg, 79104 Freiburg, Germany
| | - George Pyrowolakis
- CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany
- Institute for Biology I, Faculty of Biology, HMH, Habsburgerstr. 49, University of Freiburg, 79104 Freiburg, Germany
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8
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Aoki K, Higuchi T, Akieda Y, Matsubara K, Ohkawa Y, Ishitani T. Mechano-gradients drive morphogen-noise correction to ensure robust patterning. SCIENCE ADVANCES 2024; 10:eadp2357. [PMID: 39546611 PMCID: PMC11567007 DOI: 10.1126/sciadv.adp2357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 10/16/2024] [Indexed: 11/17/2024]
Abstract
Morphogen gradients instruct cells to pattern tissues. Although the mechanisms by which morphogens transduce chemical signals have been extensively studied, the roles and regulation of the physical communication between morphogen-receiver cells remain unclear. Here, we show that the Wnt/β-catenin-morphogen gradient, which patterns the embryonic anterior-posterior (AP) axis, generates intercellular tension gradients along the AP axis by controlling membrane cadherin levels in zebrafish embryos. This "mechano-gradient" is used for the cell competition-driven correction of noisy morphogen gradients. Naturally and artificially generated unfit cells, producing noisy Wnt/β-catenin gradients, induce local deformation of the mechano-gradients that activate mechanosensitive calcium channels in the neighboring fit cells, which then secrete annexin A1a to kill unfit cells. Thus, chemo-mechanical interconversion-mediated competitive communication between the morphogen-receiver cells ensures precise tissue patterning.
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Affiliation(s)
- Kana Aoki
- Department of Homeostatic Regulation, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Taiki Higuchi
- Department of Homeostatic Regulation, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Yuki Akieda
- Department of Homeostatic Regulation, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Kotone Matsubara
- Department of Homeostatic Regulation, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Yasuyuki Ohkawa
- Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Fukuoka, Fukuoka 812-0054, Japan
| | - Tohru Ishitani
- Department of Homeostatic Regulation, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan
- Center for Infectious Disease Education and Research (CiDER), Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan
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9
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Al Asafen H, Beseli A, Chen HY, Hiremath S, Williams CM, Reeves GT. Dynamics of BMP signaling and stable gene expression in the early Drosophila embryo. Biol Open 2024; 13:bio061646. [PMID: 39207258 PMCID: PMC11381920 DOI: 10.1242/bio.061646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 07/24/2024] [Indexed: 09/04/2024] Open
Abstract
In developing tissues, morphogen gradients are thought to initialize gene expression patterns. However, the relationship between the dynamics of morphogen-encoded signals and gene expression decisions is largely unknown. Here we examine the dynamics of the Bone Morphogenetic Protein (BMP) pathway in Drosophila blastoderm-stage embryos. In this tissue, the BMP pathway is highly dynamic: it begins as a broad and weak signal on the dorsal half of the embryo, then 20-30 min later refines into a narrow, intense peak centered on the dorsal midline. This dynamical progression of the BMP signal raises questions of how it stably activates target genes. Therefore, we performed live imaging of the BMP signal and found that dorsal-lateral cells experience only a short transient in BMP signaling, after which the signal is lost completely. Moreover, we measured the transcriptional response of the BMP target gene pannier in live embryos and found it to remain activated in dorsal-lateral cells, even after the BMP signal is lost. Our findings may suggest that the BMP pathway activates a memory, or 'ratchet' mechanism that may sustain gene expression.
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Affiliation(s)
- Hadel Al Asafen
- Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27695, USA
| | - Aydin Beseli
- Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27695, USA
| | - Hung-Yuan Chen
- Department of Chemical Engineering, Texas A&M University, College Station, TX 77843,USA
| | - Sharva Hiremath
- Department of Electrical and Computer Engineering, North Carolina State University, Raleigh, NC 27695,USA
- North Carolina Plant Sciences Initiative, North Carolina State University, Raleigh, NC 27695,USA
| | - Cranos M. Williams
- Department of Electrical and Computer Engineering, North Carolina State University, Raleigh, NC 27695,USA
- North Carolina Plant Sciences Initiative, North Carolina State University, Raleigh, NC 27695,USA
| | - Gregory T. Reeves
- Department of Chemical Engineering, Texas A&M University, College Station, TX 77843,USA
- Interdisciplinary Graduate Program in Genetics, Texas A&M University, College Station, TX 77843,USA
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10
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Hartl B, Risi S, Levin M. Evolutionary Implications of Self-Assembling Cybernetic Materials with Collective Problem-Solving Intelligence at Multiple Scales. ENTROPY (BASEL, SWITZERLAND) 2024; 26:532. [PMID: 39056895 PMCID: PMC11275831 DOI: 10.3390/e26070532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 06/10/2024] [Accepted: 06/14/2024] [Indexed: 07/28/2024]
Abstract
In recent years, the scientific community has increasingly recognized the complex multi-scale competency architecture (MCA) of biology, comprising nested layers of active homeostatic agents, each forming the self-orchestrated substrate for the layer above, and, in turn, relying on the structural and functional plasticity of the layer(s) below. The question of how natural selection could give rise to this MCA has been the focus of intense research. Here, we instead investigate the effects of such decision-making competencies of MCA agential components on the process of evolution itself, using in silico neuroevolution experiments of simulated, minimal developmental biology. We specifically model the process of morphogenesis with neural cellular automata (NCAs) and utilize an evolutionary algorithm to optimize the corresponding model parameters with the objective of collectively self-assembling a two-dimensional spatial target pattern (reliable morphogenesis). Furthermore, we systematically vary the accuracy with which the uni-cellular agents of an NCA can regulate their cell states (simulating stochastic processes and noise during development). This allows us to continuously scale the agents' competency levels from a direct encoding scheme (no competency) to an MCA (with perfect reliability in cell decision executions). We demonstrate that an evolutionary process proceeds much more rapidly when evolving the functional parameters of an MCA compared to evolving the target pattern directly. Moreover, the evolved MCAs generalize well toward system parameter changes and even modified objective functions of the evolutionary process. Thus, the adaptive problem-solving competencies of the agential parts in our NCA-based in silico morphogenesis model strongly affect the evolutionary process, suggesting significant functional implications of the near-ubiquitous competency seen in living matter.
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Affiliation(s)
- Benedikt Hartl
- Allen Discovery Center, Tufts University, Medford, MA 02155, USA;
- Institute for Theoretical Physics, Center for Computational Materials Science (CMS), TU Wien, 1040 Wien, Austria
| | - Sebastian Risi
- Digital Design, IT University of Copenhagen, 2300 Copenhagen, Denmark;
| | - Michael Levin
- Allen Discovery Center, Tufts University, Medford, MA 02155, USA;
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA
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11
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Klangprapan J, Souza GR, Ferreira JN. Bioprinting salivary gland models and their regenerative applications. BDJ Open 2024; 10:39. [PMID: 38816372 PMCID: PMC11139920 DOI: 10.1038/s41405-024-00219-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 04/29/2024] [Accepted: 04/30/2024] [Indexed: 06/01/2024] Open
Abstract
OBJECTIVE Salivary gland (SG) hypofunction is a common clinical condition arising from radiotherapy to suppress head and neck cancers. The radiation often destroys the SG secretory acini, and glands are left with limited regenerative potential. Due to the complex architecture of SG acini and ducts, three-dimensional (3D) bioprinting platforms have emerged to spatially define these in vitro epithelial units and develop mini-organs or organoids for regeneration. Due to the limited body of evidence, this comprehensive review highlights the advantages and challenges of bioprinting platforms for SG regeneration. METHODS SG microtissue engineering strategies such as magnetic 3D bioassembly of cells and microfluidic coaxial 3D bioprinting of cell-laden microfibers and microtubes have been proposed to replace the damaged acinar units, avoid the use of xenogeneic matrices (like Matrigel), and restore salivary flow. RESULTS Replacing the SG damaged organ is challenging due to its complex architecture, which combines a ductal network with acinar epithelial units to facilitate a unidirectional flow of saliva. Our research group was the first to develop 3D bioassembly SG epithelial functional organoids with innervation to respond to both cholinergic and adrenergic stimulation. More recently, microtissue engineering using coaxial 3D bioprinting of hydrogel microfibers and microtubes could also supported the formation of viable epithelial units. Both bioprinting approaches could overcome the need for Matrigel by facilitating the assembly of adult stem cells, such as human dental pulp stem cells, and primary SG cells into micro-sized 3D constructs able to produce their own matrix and self-organize into micro-modular tissue clusters with lumenized areas. Furthermore, extracellular vesicle (EV) therapies from organoid-derived secretome were also designed and validated ex vivo for SG regeneration after radiation damage. CONCLUSION Magnetic 3D bioassembly and microfluidic coaxial bioprinting platforms have the potential to create SG mini-organs for regenerative applications via organoid transplantation or organoid-derived EV therapies.
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Affiliation(s)
- Jutapak Klangprapan
- Avatar Biotechnologies for Oral Health and Healthy Longevity Research Unit, Faculty of Dentistry, Chulalongkorn University, 34 Henri-Dunant Road, Pathumwan, Bangkok, 10330, Thailand
| | - Glauco R Souza
- Greiner Bio-one North America Inc., 4238 Capital Drive, Monroe, NC, 28110, USA
| | - João N Ferreira
- Avatar Biotechnologies for Oral Health and Healthy Longevity Research Unit, Faculty of Dentistry, Chulalongkorn University, 34 Henri-Dunant Road, Pathumwan, Bangkok, 10330, Thailand.
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12
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Bhat GR, Sethi I, Sadida HQ, Rah B, Mir R, Algehainy N, Albalawi IA, Masoodi T, Subbaraj GK, Jamal F, Singh M, Kumar R, Macha MA, Uddin S, Akil ASAS, Haris M, Bhat AA. Cancer cell plasticity: from cellular, molecular, and genetic mechanisms to tumor heterogeneity and drug resistance. Cancer Metastasis Rev 2024; 43:197-228. [PMID: 38329598 PMCID: PMC11016008 DOI: 10.1007/s10555-024-10172-z] [Citation(s) in RCA: 40] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Accepted: 01/24/2024] [Indexed: 02/09/2024]
Abstract
Cancer is a complex disease displaying a variety of cell states and phenotypes. This diversity, known as cancer cell plasticity, confers cancer cells the ability to change in response to their environment, leading to increased tumor diversity and drug resistance. This review explores the intricate landscape of cancer cell plasticity, offering a deep dive into the cellular, molecular, and genetic mechanisms that underlie this phenomenon. Cancer cell plasticity is intertwined with processes such as epithelial-mesenchymal transition and the acquisition of stem cell-like features. These processes are pivotal in the development and progression of tumors, contributing to the multifaceted nature of cancer and the challenges associated with its treatment. Despite significant advancements in targeted therapies, cancer cell adaptability and subsequent therapy-induced resistance remain persistent obstacles in achieving consistent, successful cancer treatment outcomes. Our review delves into the array of mechanisms cancer cells exploit to maintain plasticity, including epigenetic modifications, alterations in signaling pathways, and environmental interactions. We discuss strategies to counteract cancer cell plasticity, such as targeting specific cellular pathways and employing combination therapies. These strategies promise to enhance the efficacy of cancer treatments and mitigate therapy resistance. In conclusion, this review offers a holistic, detailed exploration of cancer cell plasticity, aiming to bolster the understanding and approach toward tackling the challenges posed by tumor heterogeneity and drug resistance. As articulated in this review, the delineation of cellular, molecular, and genetic mechanisms underlying tumor heterogeneity and drug resistance seeks to contribute substantially to the progress in cancer therapeutics and the advancement of precision medicine, ultimately enhancing the prospects for effective cancer treatment and patient outcomes.
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Affiliation(s)
- Gh Rasool Bhat
- Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Jammu and Kashmir, India
| | - Itty Sethi
- Institute of Human Genetics, University of Jammu, Jammu, Jammu and Kashmir, India
| | - Hana Q Sadida
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar
| | - Bilal Rah
- Iron Biology Group, Research Institute of Medical and Health Science, University of Sharjah, Sharjah, UAE
| | - Rashid Mir
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Prince Fahad Bin Sultan Chair for Biomedical Research, University of Tabuk, Tabuk, Saudi Arabia
| | - Naseh Algehainy
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Prince Fahad Bin Sultan Chair for Biomedical Research, University of Tabuk, Tabuk, Saudi Arabia
| | | | - Tariq Masoodi
- Laboratory of Cancer Immunology and Genetics, Sidra Medicine, Doha, Qatar
| | | | - Farrukh Jamal
- Dr. Rammanohar, Lohia Avadh University, Ayodhya, India
| | - Mayank Singh
- Department of Medical Oncology (Lab.), Institute of Medical Sciences (AIIMS), Dr. BRAIRCH, All India, New Delhi, India
| | - Rakesh Kumar
- School of Biotechnology, Shri Mata Vaishno Devi University, Katra, Jammu and Kashmir, India
| | - Muzafar A Macha
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, Awantipora, Jammu and Kashmir, India
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
- Laboratory Animal Research Centre, Qatar University, Doha, Qatar
| | - Ammira S Al-Shabeeb Akil
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar
| | - Mohammad Haris
- Laboratory Animal Research Centre, Qatar University, Doha, Qatar.
- Center for Advanced Metabolic Imaging in Precision Medicine, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
| | - Ajaz A Bhat
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar.
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13
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Teague S, Primavera G, Chen B, Liu ZY, Yao L, Freeburne E, Khan H, Jo K, Johnson C, Heemskerk I. Time-integrated BMP signaling determines fate in a stem cell model for early human development. Nat Commun 2024; 15:1471. [PMID: 38368368 PMCID: PMC10874454 DOI: 10.1038/s41467-024-45719-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 02/02/2024] [Indexed: 02/19/2024] Open
Abstract
How paracrine signals are interpreted to yield multiple cell fate decisions in a dynamic context during human development in vivo and in vitro remains poorly understood. Here we report an automated tracking method to follow signaling histories linked to cell fate in large numbers of human pluripotent stem cells (hPSCs). Using an unbiased statistical approach, we discover that measured BMP signaling history correlates strongly with fate in individual cells. We find that BMP response in hPSCs varies more strongly in the duration of signaling than the level. However, both the level and duration of signaling activity control cell fate choices only by changing the time integral. Therefore, signaling duration and level are interchangeable in this context. In a stem cell model for patterning of the human embryo, we show that signaling histories predict the fate pattern and that the integral model correctly predicts changes in cell fate domains when signaling is perturbed. Our data suggest that mechanistically, BMP signaling is integrated by SOX2.
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Affiliation(s)
- Seth Teague
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Gillian Primavera
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Bohan Chen
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Zong-Yuan Liu
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - LiAng Yao
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Emily Freeburne
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Hina Khan
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Kyoung Jo
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Craig Johnson
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Idse Heemskerk
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA.
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA.
- Center for Cell Plasticity and Organ Design, University of Michigan Medical School, Ann Arbor, MI, USA.
- Department of Physics, University of Michigan, Ann Arbor, MI, USA.
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14
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Simon N, Safyan A, Pyrowolakis G, Matsuda S. Dally is not essential for Dpp spreading or internalization but for Dpp stability by antagonizing Tkv-mediated Dpp internalization. eLife 2024; 12:RP86663. [PMID: 38265865 PMCID: PMC10945656 DOI: 10.7554/elife.86663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2024] Open
Abstract
Dpp/BMP acts as a morphogen to provide positional information in the Drosophila wing disc. Key cell-surface molecules to control Dpp morphogen gradient formation and signaling are heparan sulfate proteoglycans (HSPGs). In the wing disc, two HSPGs, the glypicans Division abnormally delayed (Dally) and Dally-like (Dlp) have been suggested to act redundantly to control these processes through direct interaction of their heparan sulfate (HS) chains with Dpp. Based on this assumption, a number of models on how glypicans control Dpp gradient formation and signaling have been proposed, including facilitating or hindering Dpp spreading, stabilizing Dpp on the cell surface, or recycling Dpp. However, how distinct HSPGs act remains largely unknown. Here, we generate genome-engineering platforms for the two glypicans and find that only Dally is critical for Dpp gradient formation and signaling through interaction of its core protein with Dpp. We also find that this interaction is not sufficient and that the HS chains of Dally are essential for these functions largely without interacting with Dpp. We provide evidence that the HS chains of Dally are not essential for spreading or recycling of Dpp but for stabilizing Dpp on the cell surface by antagonizing receptor-mediated Dpp internalization. These results provide new insights into how distinct HSPGs control morphogen gradient formation and signaling during development.
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Affiliation(s)
- Niklas Simon
- Growth & Development, Biozentrum, Spitalstrasse, University of BaselBaselSwitzerland
| | - Abu Safyan
- International Max Planck Research School for Immunobiology, Epigenetics, and MetabolismFreiburdGermany
- Institute for Biology I, Faculty of Biology, University of FreiburgFreiburgGermany
- CIBSS – Centre for Integrative Biological Signalling Studies, University of FreiburgFreiburgGermany
- BIOSS – Centre for Biological Signalling Studies, University of FreiburgFreiburgGermany
- Hilde Mangold Haus, University of FreiburgFreiburgGermany
| | - George Pyrowolakis
- Institute for Biology I, Faculty of Biology, University of FreiburgFreiburgGermany
- CIBSS – Centre for Integrative Biological Signalling Studies, University of FreiburgFreiburgGermany
- BIOSS – Centre for Biological Signalling Studies, University of FreiburgFreiburgGermany
- Hilde Mangold Haus, University of FreiburgFreiburgGermany
| | - Shinya Matsuda
- Growth & Development, Biozentrum, Spitalstrasse, University of BaselBaselSwitzerland
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15
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Behtaj S, Karamali F, Najafian S, Masaeli E, Rybachuk M. Ciliary neurotrophic factor mediated growth of retinal ganglion cell axons on PGS/PCL scaffolds. Biomed Mater 2024; 19:025001. [PMID: 38181445 DOI: 10.1088/1748-605x/ad1bae] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 01/05/2024] [Indexed: 01/07/2024]
Abstract
Ciliary neurotrophic factor (CNTF) promotes survival and/or differentiation of a variety of neuronal cells including retinal ganglion cells (RGCs). Delivery of CNTF requires a suitable medium capable of mediating diffusion and premature release of CNTF within the target tissue. Polymeric tissue-engineered scaffolds have been readily used as substrates for cell transplantation, expansion, and differentiation and, as carriers of cell growth factors. Their functions to CNTF release for RGC proliferation have remained so far unexplored, especially to CNTF affinity to the scaffold and subsequent RGC fate. Electrospunpoly(glycerol sebacate)/poly(ϵ-caprolactone) (PGS/PCL) biopolymer scaffolds have recently shown promising results in terms of supporting regeneration of RGC neurites. This work explores covalent immobilization of CNTF on PGS/PCL scaffold and the way immobilised CNTF mediates growth of RGC axons on the scaffold. Anex-vivothree-dimensional model of rodent optic nerve on PGS/PCL revealed that RGC explants cultured in CNTF mediated environment increased their neurite extensions after 20 d of cell culture employing neurite outgrowth measurements. The CNTF secretion on PGS/PCL scaffold was found bio-mimicking natural extracellular matrix of the cell target tissue and, consequently, has shown a potential to improve the overall efficacy of the RGC regeneration process.
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Affiliation(s)
- Sanaz Behtaj
- School of Engineering and Built Environment, Griffith University, Engineering Drive, Southport QLD 4222, Australia
- Department of Animal Biotechnology, Cell Science Research Centre, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
- Clem Jones Centre for Neurobiology and Stem Cell Research, Menzies Health Institute Queensland, Griffith University, Gold Coast QLD 4222, Australia
| | - Fereshteh Karamali
- Department of Animal Biotechnology, Cell Science Research Centre, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Samaneh Najafian
- Department of Animal Biotechnology, Cell Science Research Centre, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Elahe Masaeli
- Department of Animal Biotechnology, Cell Science Research Centre, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Maksym Rybachuk
- School of Engineering and Built Environment, Griffith University, 170 Kessels Road, Nathan QLD 4111, Australia
- Centre for Quantum Dynamics and Australian Attosecond Science Facility, Griffith University, Science Road, Nathan QLD 4111, Australia
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16
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Chitra U, Arnold BJ, Sarkar H, Ma C, Lopez-Darwin S, Sanno K, Raphael BJ. Mapping the topography of spatial gene expression with interpretable deep learning. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.10.561757. [PMID: 37873258 PMCID: PMC10592770 DOI: 10.1101/2023.10.10.561757] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Abstract
Spatially resolved transcriptomics technologies provide high-throughput measurements of gene expression in a tissue slice, but the sparsity of this data complicates the analysis of spatial gene expression patterns such as gene expression gradients. We address these issues by deriving a topographic map of a tissue slice-analogous to a map of elevation in a landscape-using a novel quantity called the isodepth. Contours of constant isodepth enclose spatial domains with distinct cell type composition, while gradients of the isodepth indicate spatial directions of maximum change in gene expression. We develop GASTON, an unsupervised and interpretable deep learning algorithm that simultaneously learns the isodepth, spatial gene expression gradients, and piecewise linear functions of the isodepth that model both continuous gradients and discontinuous spatial variation in the expression of individual genes. We validate GASTON by showing that it accurately identifies spatial domains and marker genes across several biological systems. In SRT data from the brain, GASTON reveals gradients of neuronal differentiation and firing, and in SRT data from a tumor sample, GASTON infers gradients of metabolic activity and epithelial-mesenchymal transition (EMT)-related gene expression in the tumor microenvironment.
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Affiliation(s)
- Uthsav Chitra
- Department of Computer Science, Princeton University, Princeton, NJ, USA
| | - Brian J. Arnold
- Department of Computer Science, Princeton University, Princeton, NJ, USA
- Center for Statistics and Machine Learning, Princeton University, Princeton, NJ, USA
| | - Hirak Sarkar
- Department of Computer Science, Princeton University, Princeton, NJ, USA
- Ludwig Cancer Institute, Princeton Branch, Princeton University, Princeton, NJ, USA
| | - Cong Ma
- Department of Computer Science, Princeton University, Princeton, NJ, USA
| | | | - Kohei Sanno
- Department of Computer Science, Princeton University, Princeton, NJ, USA
- Center for Statistics and Machine Learning, Princeton University, Princeton, NJ, USA
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17
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Matsuda S, Affolter M. Is Drosophila Dpp/BMP morphogen spreading required for wing patterning and growth? Bioessays 2023; 45:e2200218. [PMID: 37452394 DOI: 10.1002/bies.202200218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 06/02/2023] [Accepted: 06/15/2023] [Indexed: 07/18/2023]
Abstract
Secreted signaling molecules act as morphogens to control patterning and growth in many developing tissues. Since locally produced morphogens spread to form a concentration gradient in the surrounding tissue, spreading is generally thought to be the key step in the non-autonomous actions. Here, we review recent advances in tool development to investigate morphogen function using the role of decapentaplegic (Dpp)/bone morphogenetic protein (BMP)-type ligand in the Drosophila wing disc as an example. By applying protein binder tools to distinguish between the roles of Dpp spreading and local Dpp signaling, we found that Dpp signaling in the source cells is important for wing patterning and growth but Dpp spreading from this source cells is not as strictly required as previously thought. Given recent studies showing unexpected requirements of long-range action of different morphogens, manipulating endogenous morphogen gradients by synthetic protein binder tools could shed more light on how morphogens act in developing tissues.
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Affiliation(s)
- Shinya Matsuda
- Growth & Development, Biozentrum, University of Basel, Basel, Switzerland
| | - Markus Affolter
- Growth & Development, Biozentrum, University of Basel, Basel, Switzerland
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18
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Kyomen S, Murillo-Rincón AP, Kaucká M. Evolutionary mechanisms modulating the mammalian skull development. Philos Trans R Soc Lond B Biol Sci 2023; 378:20220080. [PMID: 37183900 PMCID: PMC10184257 DOI: 10.1098/rstb.2022.0080] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2023] Open
Abstract
Mammals possess impressive craniofacial variation that mirrors their adaptation to diverse ecological niches, feeding behaviour, physiology and overall lifestyle. The spectrum of craniofacial geometries is established mainly during embryonic development. The formation of the head represents a sequence of events regulated on genomic, molecular, cellular and tissue level, with each step taking place under tight spatio-temporal control. Even minor variations in timing, position or concentration of the molecular drivers and the resulting events can affect the final shape, size and position of the skeletal elements and the geometry of the head. Our knowledge of craniofacial development increased substantially in the last decades, mainly due to research using conventional vertebrate model organisms. However, how developmental differences in head formation arise specifically within mammals remains largely unexplored. This review highlights three evolutionary mechanisms acknowledged to modify ontogenesis: heterochrony, heterotopy and heterometry. We present recent research that links changes in developmental timing, spatial organization or gene expression levels to the acquisition of species-specific skull morphologies. We highlight how these evolutionary modifications occur on the level of the genes, molecules and cellular processes, and alter conserved developmental programmes to generate a broad spectrum of skull shapes characteristic of the class Mammalia. This article is part of the theme issue 'The mammalian skull: development, structure and function'.
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Affiliation(s)
- Stella Kyomen
- Max Planck Institute for Evolutionary Biology, August-Thienemann-Strasse 2, Plön 24306, Germany
| | - Andrea P Murillo-Rincón
- Max Planck Institute for Evolutionary Biology, August-Thienemann-Strasse 2, Plön 24306, Germany
| | - Markéta Kaucká
- Max Planck Institute for Evolutionary Biology, August-Thienemann-Strasse 2, Plön 24306, Germany
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19
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Zhou Z, Lin N, Ouyang Y, Liu S, Zhang Y, Willner I. Cascaded, Feedback-Driven, and Spatially Localized Emergence of Constitutional Dynamic Networks Driven by Enzyme-Free Catalytic DNA Circuits. J Am Chem Soc 2023. [PMID: 37257165 DOI: 10.1021/jacs.3c02083] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
The enzyme-free catalytic hairpin assembly (CHA) process is introduced as a functional reaction module for guided, high-throughput, emergence, and evolution of constitutional dynamic networks, CDNs, from a set of nucleic acids. The process is applied to assemble networks of variable complexities, functionalities, and spatial confinement, and the systems provide possible mechanistic pathways for the evolution of dynamic networks under prebiotic conditions. Subjecting a set of four or six structurally engineered hairpins to a promoter P1 leads to the CHA-guided emergence of a [2 × 2] CDN or the evolution of a [3 × 3] CDN, respectively. Reacting of a set of branched three-arm DNA-hairpin-functionalized junctions to the promoter strand activates the CHA-induced emergence of a three-dimensional (3D) CDN framework emulating native gene regulatory networks. In addition, activation of a two-layer CHA cascade circuit or a cross-catalytic CHA circuit and cascaded driving feedback-driven evolution of CDNs are demonstrated. Also, subjecting a four-hairpin-modified DNA tetrahedron nanostructure to an auxiliary promoter strand simulates the evolution of a dynamically equilibrated DNA tetrahedron-based CDN that undergoes secondary fueled dynamic reconfiguration. Finally, the effective permeation of DNA tetrahedron structures into cells is utilized to integrate the four-hairpin-functionalized tetrahedron reaction module into cells. The spatially localized miRNA-triggered CHA evolution and reconfiguration of CDNs allowed the logic-gated imaging of intracellular RNAs. Beyond the bioanalytical applications of the systems, the study introduces possible mechanistic pathways for the evolution of functional networks under prebiotic conditions.
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Affiliation(s)
- Zhixin Zhou
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China
| | - Nina Lin
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China
| | - Yu Ouyang
- Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
| | - Songqin Liu
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China
| | - Yuanjian Zhang
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China
| | - Itamar Willner
- Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
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20
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Pierini G, Dahmann C. Hedgehog morphogen gradient is robust towards variations in tissue morphology in Drosophila. Sci Rep 2023; 13:8454. [PMID: 37231029 DOI: 10.1038/s41598-023-34632-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 05/04/2023] [Indexed: 05/27/2023] Open
Abstract
During tissue development, gradients of secreted signaling molecules known as morphogens provide cells with positional information. The mechanisms underlying morphogen spreading have been widely studied, however, it remains largely unexplored whether the shape of morphogen gradients is influenced by tissue morphology. Here, we developed an analysis pipeline to quantify the distribution of proteins within a curved tissue. We applied it to the Hedgehog morphogen gradient in the Drosophila wing and eye-antennal imaginal discs, which are flat and curved tissues, respectively. Despite a different expression profile, the slope of the Hedgehog gradient was comparable between the two tissues. Moreover, inducing ectopic folds in wing imaginal discs did not affect the slope of the Hedgehog gradient. Suppressing curvature in the eye-antennal imaginal disc also did not alter the Hedgehog gradient slope but led to ectopic Hedgehog expression. In conclusion, through the development of an analysis pipeline that allows quantifying protein distribution in curved tissues, we show that the Hedgehog gradient is robust towards variations in tissue morphology.
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Affiliation(s)
- Giulia Pierini
- School of Science, Technische Universität Dresden, 01062, Dresden, Germany
| | - Christian Dahmann
- School of Science, Technische Universität Dresden, 01062, Dresden, Germany.
- Cluster of Excellence Physics of Life, Technische Universität Dresden, 01062, Dresden, Germany.
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21
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Baier F, Gauye F, Perez-Carrasco R, Payne JL, Schaerli Y. Environment-dependent epistasis increases phenotypic diversity in gene regulatory networks. SCIENCE ADVANCES 2023; 9:eadf1773. [PMID: 37224262 DOI: 10.1126/sciadv.adf1773] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 04/17/2023] [Indexed: 05/26/2023]
Abstract
Mutations to gene regulatory networks can be maladaptive or a source of evolutionary novelty. Epistasis confounds our understanding of how mutations affect the expression patterns of gene regulatory networks, a challenge exacerbated by the dependence of epistasis on the environment. We used the toolkit of synthetic biology to systematically assay the effects of pairwise and triplet combinations of mutant genotypes on the expression pattern of a gene regulatory network expressed in Escherichia coli that interprets an inducer gradient across a spatial domain. We uncovered a preponderance of epistasis that can switch in magnitude and sign across the inducer gradient to produce a greater diversity of expression pattern phenotypes than would be possible in the absence of such environment-dependent epistasis. We discuss our findings in the context of the evolution of hybrid incompatibilities and evolutionary novelties.
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Affiliation(s)
- Florian Baier
- Department of Fundamental Microbiology, University of Lausanne, Biophore Building, 1015 Lausanne, Switzerland
| | - Florence Gauye
- Department of Fundamental Microbiology, University of Lausanne, Biophore Building, 1015 Lausanne, Switzerland
| | | | - Joshua L Payne
- Institute of Integrative Biology, ETH Zurich, 8092 Zurich, Switzerland
| | - Yolanda Schaerli
- Department of Fundamental Microbiology, University of Lausanne, Biophore Building, 1015 Lausanne, Switzerland
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22
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Teague S, Primavera G, Chen B, Freeburne E, Khan H, Jo K, Johnson C, Heemskerk I. The time integral of BMP signaling determines fate in a stem cell model for early human development. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.10.536068. [PMID: 37090515 PMCID: PMC10120633 DOI: 10.1101/2023.04.10.536068] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/25/2023]
Abstract
How paracrine signals are interpreted to yield multiple cell fate decisions in a dynamic context during human development in vivo and in vitro remains poorly understood. Here we report an automated tracking method to follow signaling histories linked to cell fate in large numbers of human pluripotent stem cells (hPSCs). Using an unbiased statistical approach, we discovered that measured BMP signaling history correlates strongly with fate in individual cells. We found that BMP response in hPSCs varies more strongly in the duration of signaling than the level. However, we discovered that both the level and duration of signaling activity control cell fate choices only by changing the time integral of signaling and that duration and level are therefore interchangeable in this context. In a stem cell model for patterning of the human embryo, we showed that signaling histories predict the fate pattern and that the integral model correctly predicts changes in cell fate domains when signaling is perturbed. Using an RNA-seq screen we then found that mechanistically, BMP signaling is integrated by SOX2.
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Affiliation(s)
- Seth Teague
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
| | - Gillian Primavera
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
| | - Bohan Chen
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan
| | - Emily Freeburne
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Hina Khan
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Kyoung Jo
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Craig Johnson
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Idse Heemskerk
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan
- Center for Cell Plasticity and Organ Design, University of Michigan Medical School, Ann Arbor, Michigan
- Department of Physics, University of Michigan, Ann Arbor, Michigan
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23
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Kuyyamudi C, Menon SN, Sinha S. Precision of morphogen-driven tissue patterning during development is enhanced through contact-mediated cellular interactions. Phys Rev E 2023; 107:024407. [PMID: 36932610 DOI: 10.1103/physreve.107.024407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 01/30/2023] [Indexed: 06/18/2023]
Abstract
Cells in developing embryos reliably differentiate to attain location-specific fates, despite fluctuations in morphogen concentrations that provide positional information and in molecular processes that interpret it. We show that local contact-mediated cell-cell interactions utilize inherent asymmetry in the response of patterning genes to the global morphogen signal yielding a bimodal response. This results in robust developmental outcomes with a consistent identity for the dominant gene at each cell, substantially reducing the uncertainty in the location of boundaries between distinct fates.
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Affiliation(s)
- Chandrashekar Kuyyamudi
- The Institute of Mathematical Sciences, CIT Campus, Taramani, Chennai 600113, India
- Homi Bhabha National Institute, Anushaktinagar, Mumbai 400 094, India
| | - Shakti N Menon
- The Institute of Mathematical Sciences, CIT Campus, Taramani, Chennai 600113, India
| | - Sitabhra Sinha
- The Institute of Mathematical Sciences, CIT Campus, Taramani, Chennai 600113, India
- Homi Bhabha National Institute, Anushaktinagar, Mumbai 400 094, India
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24
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Saha S, Pradhan N, B N, Mahadevappa R, Minocha S, Kumar S. Cancer plasticity: Investigating the causes for this agility. Semin Cancer Biol 2023; 88:138-156. [PMID: 36584960 DOI: 10.1016/j.semcancer.2022.12.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 12/09/2022] [Accepted: 12/19/2022] [Indexed: 12/30/2022]
Abstract
Cancer is not a hard-wired phenomenon but an evolutionary disease. From the onset of carcinogenesis, cancer cells continuously adapt and evolve to satiate their ever-growing proliferation demands. This results in the formation of multiple subtypes of cancer cells with different phenotypes, cellular compositions, and consequently displaying varying degrees of tumorigenic identity and function. This phenomenon is referred to as cancer plasticity, during which the cancer cells exist in a plethora of cellular states having distinct phenotypes. With the advent of modern technologies equipped with enhanced resolution and depth, for example, single-cell RNA-sequencing and advanced computational tools, unbiased cancer profiling at a single-cell resolution are leading the way in understanding cancer cell rewiring both spatially and temporally. In this review, the processes and mechanisms that give rise to cancer plasticity include both intrinsic genetic factors such as epigenetic changes, differential expression due to changes in DNA, RNA, or protein content within the cancer cell, as well as extrinsic environmental factors such as tissue perfusion, extracellular milieu are detailed and their influence on key cancer plasticity hallmarks such as epithelial-mesenchymal transition (EMT) and cancer cell stemness (CSCs) are discussed. Due to therapy evasion and drug resistance, tumor heterogeneity caused by cancer plasticity has major therapeutic ramifications. Hence, it is crucial to comprehend all the cellular and molecular mechanisms that control cellular plasticity. How this process evades therapy, and the therapeutic avenue of targeting cancer plasticity must be diligently investigated.
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Affiliation(s)
- Shubhraneel Saha
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India
| | - Nikita Pradhan
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India
| | - Neha B
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India
| | - Ravikiran Mahadevappa
- Department of Biotechnology, School of Science, Gandhi Institute of Technology and Management, Deemed to be University, Bengaluru, Karnataka 562163, India
| | - Shilpi Minocha
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India.
| | - Saran Kumar
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India.
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25
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Wang S, Tanaka Y, Xu Y, Takeda S, Hirokawa N. KIF3B promotes a PI3K signaling gradient causing changes in a Shh protein gradient and suppressing polydactyly in mice. Dev Cell 2022; 57:2273-2289.e11. [DOI: 10.1016/j.devcel.2022.09.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 07/27/2022] [Accepted: 09/13/2022] [Indexed: 11/03/2022]
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Abstract
Metazoan embryos develop from a single cell into three-dimensional structured organisms while groups of genetically identical cells attain specialized identities. Cells of the developing embryo both create and accurately interpret morphogen gradients to determine their positions and make specific decisions in response. Here, we first cover intellectual roots of morphogen and positional information concepts. Focusing on animal embryos, we then provide a review of current understanding on how morphogen gradients are established and how their spans are controlled. Lastly, we cover how gradients evolve in time and space during development, and how they encode information to control patterning. In sum, we provide a list of patterning principles for morphogen gradients and review recent advances in quantitative methodologies elucidating information provided by morphogens.
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Affiliation(s)
- M. Fethullah Simsek
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Ertuğrul M. Özbudak
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
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27
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Yu X, Deng Z, Li H, Ma Y, Ma X, Zheng Q. Anisotropic hydrogel fabricated by controlled diffusion as a bio-scaffold for the regeneration of cartilage injury. RSC Adv 2022; 12:28254-28263. [PMID: 36320226 PMCID: PMC9535635 DOI: 10.1039/d2ra05141a] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 09/22/2022] [Indexed: 11/05/2022] Open
Abstract
Controlled fabrication of anisotropic materials has become a hotspot in materials science, particularly biomaterials, since the next generation of tissue engineering is based on the application of heterogeneous structures that can simulate the original biological complexity of the body. The current fabrication method of producing anisotropic materials involves expensive and highly specialized equipment, and not every conventional method can be applied to preparing anisotropic materials for corresponding tissue engineering. Anisotropic materials can be easily applied to a problem in tissue engineering: cartilage injury repairing. The articular cartilage consists of four spatially distinct regions: superficial, transitional, deep, and calcified. Each region has a specific extracellular matrix composition, mechanical properties, and cellular organization; this calls for the application of an anisotropic hydrogel. Controlled diffusion, under the assistance of buoyancy, has been considered a generalized method to prepare materials using a gradient. The diffusion of two solutions can be controlled through the difference in their densities. In addition to providing anisotropy, this method realizes the in situ formation of an anisotropic hydrogel, and simplifies the preparation process, freeing it from the need for expensive equipment such as 3D printing and microfluidics. Herein, an anisotropic hydrogel based on a decellularized extracellular matrix is fabricated and characterized. The as-prepared scaffold possessed specific chemical composition, physical properties, and physiological factor gradient. In vitro experiments ensured its biocompatibility and biological effectiveness; further in vivo experiments confirmed its application in the effective regeneration of cartilage injury.
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Affiliation(s)
- Xiaotian Yu
- Department of Orthopedics, Guangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesChina,Guangdong Cardiovascular InstituteGuangzhouGuangdongChina,CBSR&NLPR, Institute of Automation, Chinese Academy of SciencesBeijingChina
| | - Zhantao Deng
- Department of Orthopedics, Guangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesChina
| | - Han Li
- Department of Orthopedics, Guangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesChina,Guangdong Cardiovascular InstituteGuangzhouGuangdongChina
| | - Yuanchen Ma
- Department of Orthopedics, Guangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesChina
| | - Xibo Ma
- CBSR&NLPR, Institute of Automation, Chinese Academy of SciencesBeijingChina,School of Artificial Intelligence, University of Chinese Academy of SciencesBeijingChina
| | - Qiujian Zheng
- Department of Orthopedics, Guangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesChina,The Second School of Clinical Medicine, Southern Medical UniversityChina
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28
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Yao YX, Dong JQ, Zhu JY, Huang L, Pei DQ, Lai YC. Beyond Boolean: Ternary networks and dynamics. CHAOS (WOODBURY, N.Y.) 2022; 32:083117. [PMID: 36049930 DOI: 10.1063/5.0097874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 07/06/2022] [Indexed: 06/15/2023]
Abstract
Boolean networks introduced by Kauffman, originally intended as a prototypical model for gaining insights into gene regulatory dynamics, have become a paradigm for understanding a variety of complex systems described by binary state variables. However, there are situations, e.g., in biology, where a binary state description of the underlying dynamical system is inadequate. We propose random ternary networks and investigate the general dynamical properties associated with the ternary discretization of the variables. We find that the ternary dynamics can be either ordered or disordered with a positive Lyapunov exponent, and the boundary between them in the parameter space can be determined analytically. A dynamical event that is key to determining the boundary is the emergence of an additional fixed point for which we provide numerical verification. We also find that the nodes playing a pivotal role in shaping the system dynamics have characteristically distinct behaviors in different regions of the parameter space, and, remarkably, the boundary between these regions coincides with that separating the ordered and disordered dynamics. Overall, our framework of ternary networks significantly broadens the classical Boolean paradigm by enabling a quantitative description of richer and more complex dynamical behaviors.
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Affiliation(s)
- Yu-Xiang Yao
- Lanzhou Center for Theoretical Physics and Key Laboratory of Theoretical Physics of Gansu Province, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Jia-Qi Dong
- Lanzhou Center for Theoretical Physics and Key Laboratory of Theoretical Physics of Gansu Province, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Jie-Ying Zhu
- South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China
| | - Liang Huang
- Lanzhou Center for Theoretical Physics and Key Laboratory of Theoretical Physics of Gansu Province, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Duan-Qing Pei
- Laboratory of Cell Fate Control, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China
| | - Ying-Cheng Lai
- School of Electrical, Computer and Energy Engineering, Arizona State University, Tempe, Arizona 85287, USA
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29
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Dolnik M, Konow C, Somberg NH, Epstein IR. Effect of obstructions on growing Turing patterns. CHAOS (WOODBURY, N.Y.) 2022; 32:073127. [PMID: 35907715 DOI: 10.1063/5.0099753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 06/27/2022] [Indexed: 06/15/2023]
Abstract
We study how Turing pattern formation on a growing domain is affected by discrete domain discontinuities. We use the Lengyel-Epstein reaction-diffusion model to numerically simulate Turing pattern formation on radially expanding circular domains containing a variety of obstruction geometries, including obstructions spanning the length of the domain, such as walls and slits, and local obstructions, such as small blocks. The pattern formation is significantly affected by the obstructions, leading to novel pattern morphologies. We show that obstructions can induce growth mode switching and disrupt local pattern formation and that these effects depend on the shape and placement of the objects as well as the domain growth rate. This work provides a customizable framework to perform numerical simulations on different types of obstructions and other heterogeneous domains, which may guide future numerical and experimental studies. These results may also provide new insights into biological pattern growth and formation, especially in non-idealized domains containing noise or discontinuities.
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Affiliation(s)
- Milos Dolnik
- Department of Chemistry, MS 015, Brandeis University, Waltham, Massachusetts 02453, USA
| | - Christopher Konow
- Department of Chemistry, MS 015, Brandeis University, Waltham, Massachusetts 02453, USA
| | - Noah H Somberg
- Department of Chemistry, MS 015, Brandeis University, Waltham, Massachusetts 02453, USA
| | - Irving R Epstein
- Department of Chemistry, MS 015, Brandeis University, Waltham, Massachusetts 02453, USA
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30
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Savoj S, Esfahani MHN, Karimi A, Karamali F. Integrated stem cells from apical papilla in a 3D culture system improve human embryonic stem cell derived retinal organoid formation. Life Sci 2022; 291:120273. [PMID: 35016877 DOI: 10.1016/j.lfs.2021.120273] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 12/15/2021] [Accepted: 12/23/2021] [Indexed: 01/08/2023]
Abstract
AIM Eye organoids are 3D models of the retina that provide new possibilities for studying retinal development, drug toxicity and the molecular mechanisms of diseases. Although there are several protocols that can be used to generate functional tissues, none have been used to assemble human retinal organoids containing mesenchymal stem cells (MSCs). MAIN METHODS In this study we intend to assess the effective interactions of MSCs and human embryonic stem cells (hESCs) during retinal organoid formation. We evaluated the inducing activities of bone marrow MSCs (BM-MSCs), trabecular meshwork (TM), and stem cells from apical papilla (SCAP)-derived MSCs in differentiation of hESCs in a three-dimensional (3D) direct co-culture system. KEY FINDINGS In comparison with the two other MSC sources, the induction potential of SCAP was confirmed in the co-culture system. Although the different SCAP cell ratios did not show any significant morphology changes during the first seven days, increasing the number of SCAPs improved formation of the optic vesicle (OV) structure, which was confirmed by assessment of specific markers. The OVs subsequently developed to an optic cup (OC), which was similar to the in vivo environment. These arrangements expressed MITF in the outer layer and CHX10 in the inner layer. SIGNIFICANCE We assessed the inducing activity of SCAP during differentiation of hESCs towards a retinal fate in a 3D organoid system. However, future studies be conducted to gather additional details about the development of the eye field, retinal differentiation, and the molecular mechanisms of diseases.
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Affiliation(s)
- Soraya Savoj
- Department of Biology, University of Payam Noor, Isfahan, Iran; Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Mohammad Hossein Nasr Esfahani
- Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Akbar Karimi
- Department of Biology, University of Payam Noor, Isfahan, Iran.
| | - Fereshteh Karamali
- Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran.
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31
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Yu W, Li S, Guan X, Zhang N, Xie X, Zhang K, Bai Y. Higher yield and enhanced therapeutic effects of exosomes derived from MSCs in hydrogel-assisted 3D culture system for bone regeneration. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2022; 133:112646. [DOI: 10.1016/j.msec.2022.112646] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 12/09/2021] [Accepted: 01/03/2022] [Indexed: 02/07/2023]
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32
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Matsuda S, Schaefer JV, Mii Y, Hori Y, Bieli D, Taira M, Plückthun A, Affolter M. Asymmetric requirement of Dpp/BMP morphogen dispersal in the Drosophila wing disc. Nat Commun 2021; 12:6435. [PMID: 34750371 PMCID: PMC8576045 DOI: 10.1038/s41467-021-26726-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 10/20/2021] [Indexed: 11/26/2022] Open
Abstract
How morphogen gradients control patterning and growth in developing tissues remains largely unknown due to lack of tools manipulating morphogen gradients. Here, we generate two membrane-tethered protein binders that manipulate different aspects of Decapentaplegic (Dpp), a morphogen required for overall patterning and growth of the Drosophila wing. One is "HA trap" based on a single-chain variable fragment (scFv) against the HA tag that traps HA-Dpp to mainly block its dispersal, the other is "Dpp trap" based on a Designed Ankyrin Repeat Protein (DARPin) against Dpp that traps Dpp to block both its dispersal and signaling. Using these tools, we found that, while posterior patterning and growth require Dpp dispersal, anterior patterning and growth largely proceed without Dpp dispersal. We show that dpp transcriptional refinement from an initially uniform to a localized expression and persistent signaling in transient dpp source cells render the anterior compartment robust against the absence of Dpp dispersal. Furthermore, despite a critical requirement of dpp for the overall wing growth, neither Dpp dispersal nor direct signaling is critical for lateral wing growth after wing pouch specification. These results challenge the long-standing dogma that Dpp dispersal is strictly required to control and coordinate overall wing patterning and growth.
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Affiliation(s)
| | - Jonas V Schaefer
- Department of Biochemistry, University of Zurich, Zurich, Switzerland
| | - Yusuke Mii
- National Institute for Basic Biology and Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, Okazaki, Aichi, Japan
- JST PRESTO, Kawaguchi, Saitama, Japan
| | - Yutaro Hori
- Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, Japan
| | | | - Masanori Taira
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan
- Department of Biological Sciences, Faculty of Science and Engineering, Chuo University, Tokyo, Japan
| | - Andreas Plückthun
- Department of Biochemistry, University of Zurich, Zurich, Switzerland
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33
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Guglielmi L, Heliot C, Kumar S, Alexandrov Y, Gori I, Papaleonidopoulou F, Barrington C, East P, Economou AD, French PMW, McGinty J, Hill CS. Smad4 controls signaling robustness and morphogenesis by differentially contributing to the Nodal and BMP pathways. Nat Commun 2021; 12:6374. [PMID: 34737283 PMCID: PMC8569018 DOI: 10.1038/s41467-021-26486-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 10/07/2021] [Indexed: 12/25/2022] Open
Abstract
The transcriptional effector SMAD4 is a core component of the TGF-β family signaling pathways. However, its role in vertebrate embryo development remains unresolved. To address this, we deleted Smad4 in zebrafish and investigated the consequences of this on signaling by the TGF-β family morphogens, BMPs and Nodal. We demonstrate that in the absence of Smad4, dorsal/ventral embryo patterning is disrupted due to the loss of BMP signaling. However, unexpectedly, Nodal signaling is maintained, but lacks robustness. This Smad4-independent Nodal signaling is sufficient for mesoderm specification, but not for optimal endoderm specification. Furthermore, using Optical Projection Tomography in combination with 3D embryo morphometry, we have generated a BMP morphospace and demonstrate that Smad4 mutants are morphologically indistinguishable from embryos in which BMP signaling has been genetically/pharmacologically perturbed. Smad4 is thus differentially required for signaling by different TGF-β family ligands, which has implications for diseases where Smad4 is mutated or deleted.
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Affiliation(s)
- Luca Guglielmi
- Developmental Signalling Laboratory, The Francis Crick Institute, London, NW1 1AT, UK
| | - Claire Heliot
- Developmental Signalling Laboratory, The Francis Crick Institute, London, NW1 1AT, UK
| | - Sunil Kumar
- Advanced Light Microscopy, The Francis Crick Institute, London, NW1 1AT, UK
| | - Yuriy Alexandrov
- Advanced Light Microscopy, The Francis Crick Institute, London, NW1 1AT, UK
| | - Ilaria Gori
- Developmental Signalling Laboratory, The Francis Crick Institute, London, NW1 1AT, UK
| | | | - Christopher Barrington
- Bioinformatics and Biostatistics Facility, The Francis Crick Institute, London, NW1 1AT, UK
| | - Philip East
- Bioinformatics and Biostatistics Facility, The Francis Crick Institute, London, NW1 1AT, UK
| | - Andrew D Economou
- Developmental Signalling Laboratory, The Francis Crick Institute, London, NW1 1AT, UK
| | - Paul M W French
- Department of Physics, Imperial College London, SW7 2AZ, London, UK
| | - James McGinty
- Department of Physics, Imperial College London, SW7 2AZ, London, UK
| | - Caroline S Hill
- Developmental Signalling Laboratory, The Francis Crick Institute, London, NW1 1AT, UK.
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34
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Dubay R, Urban JN, Darling EM. Single-Cell Microgels for Diagnostics and Therapeutics. ADVANCED FUNCTIONAL MATERIALS 2021; 31:2009946. [PMID: 36329867 PMCID: PMC9629779 DOI: 10.1002/adfm.202009946] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Indexed: 05/14/2023]
Abstract
Cell encapsulation within hydrogel droplets is transforming what is feasible in multiple fields of biomedical science such as tissue engineering and regenerative medicine, in vitro modeling, and cell-based therapies. Recent advances have allowed researchers to miniaturize material encapsulation complexes down to single-cell scales, where each complex, termed a single-cell microgel, contains only one cell surrounded by a hydrogel matrix while remaining <100 μm in size. With this achievement, studies requiring single-cell resolution are now possible, similar to those done using liquid droplet encapsulation. Of particular note, applications involving long-term in vitro cultures, modular bioinks, high-throughput screenings, and formation of 3D cellular microenvironments can be tuned independently to suit the needs of individual cells and experimental goals. In this progress report, an overview of established materials and techniques used to fabricate single-cell microgels, as well as insight into potential alternatives is provided. This focused review is concluded by discussing applications that have already benefited from single-cell microgel technologies, as well as prospective applications on the cusp of achieving important new capabilities.
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Affiliation(s)
- Ryan Dubay
- Center for Biomedical Engineering, Brown University, 175 Meeting St., Providence, RI 02912, USA
- Draper, 555 Technology Sq., Cambridge, MA 02139, USA
| | - Joseph N Urban
- Center for Biomedical Engineering, Brown University, 175 Meeting St., Providence, RI 02912, USA
| | - Eric M Darling
- Department of Molecular Pharmacology, Physiology, and Biotechnology, Center for Biomedical Engineering, School of Engineering, Department of Orthopaedics, Brown University, 175 Meeting St., Providence, RI 02912, USA
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35
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Zhang L, Perez-Romero C, Dostatni N, Fradin C. Using FCS to accurately measure protein concentration in the presence of noise and photobleaching. Biophys J 2021; 120:4230-4241. [PMID: 34242593 PMCID: PMC8516637 DOI: 10.1016/j.bpj.2021.06.035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 06/02/2021] [Accepted: 06/28/2021] [Indexed: 11/24/2022] Open
Abstract
Quantitative cell biology requires precise and accurate concentration measurements, resolved both in space and time. Fluorescence correlation spectroscopy (FCS) has been held as a promising technique to perform such measurements because the fluorescence fluctuations it relies on are directly dependent on the absolute number of fluorophores in the detection volume. However, the most interesting applications are in cells, where autofluorescence and confinement result in strong background noise and important levels of photobleaching. Both noise and photobleaching introduce systematic bias in FCS concentration measurements and need to be corrected for. Here, we propose to make use of the photobleaching inevitably occurring in confined environments to perform series of FCS measurements at different fluorophore concentration, which we show allows a precise in situ measurement of both background noise and molecular brightness. Such a measurement can then be used as a calibration to transform confocal intensity images into concentration maps. The power of this approach is first illustrated with in vitro measurements using different dye solutions, then its applicability for in vivo measurements is demonstrated in Drosophila embryos for a model nuclear protein and for two morphogens, Bicoid and Capicua.
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Affiliation(s)
- Lili Zhang
- Department of Physics and Astronomy, McMaster University, Hamilton, Ontario, Canada
| | - Carmina Perez-Romero
- Department of Physics and Astronomy, McMaster University, Hamilton, Ontario, Canada; Institut Curie, PSL University, CNRS, Paris, France; Nuclear Dynamics, Sorbonne University, Paris, France
| | - Nathalie Dostatni
- Institut Curie, PSL University, CNRS, Paris, France; Nuclear Dynamics, Sorbonne University, Paris, France
| | - Cécile Fradin
- Department of Physics and Astronomy, McMaster University, Hamilton, Ontario, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
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36
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Control of vein-forming, striped gene expression by auxin signaling. BMC Biol 2021; 19:213. [PMID: 34556094 PMCID: PMC8461865 DOI: 10.1186/s12915-021-01143-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 09/03/2021] [Indexed: 11/10/2022] Open
Abstract
Background Activation of gene expression in striped domains is a key building block of biological patterning, from the recursive formation of veins in plant leaves to that of ribs and vertebrae in our bodies. In animals, gene expression is activated in striped domains by the differential affinity of broadly expressed transcription factors for their target genes and the combinatorial interaction between such target genes. In plants, how gene expression is activated in striped domains is instead unknown. We address this question for the broadly expressed MONOPTEROS (MP) transcription factor and its target gene ARABIDOPSIS THALIANA HOMEOBOX FACTOR8 (ATHB8). Results We find that ATHB8 promotes vein formation and that such vein-forming function depends on both levels of ATHB8 expression and width of ATHB8 expression domains. We further find that ATHB8 expression is activated in striped domains by a combination of (1) activation of ATHB8 expression through binding of peak levels of MP to a low-affinity MP-binding site in the ATHB8 promoter and (2) repression of ATHB8 expression by MP target genes of the AUXIN/INDOLE-3-ACETIC-ACID-INDUCIBLE family. Conclusions Our findings suggest that a common regulatory logic controls activation of gene expression in striped domains in both plants and animals despite the independent evolution of their multicellularity. Supplementary Information The online version contains supplementary material available at 10.1186/s12915-021-01143-9.
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37
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Abstract
Plants exhibit remarkable lineage plasticity, allowing them to regenerate organs that differ from their respective origins. Such developmental plasticity is dependent on the activity of pluripotent founder cells or stem cells residing in meristems. At the shoot apical meristem (SAM), the constant flow of cells requires continuing cell specification governed by a complex genetic network, with the WUSCHEL transcription factor and phytohormone cytokinin at its core. In this review, I discuss some intriguing recent discoveries that expose new principles and mechanisms of patterning and cell specification acting both at the SAM and, prior to meristem organogenesis during shoot regeneration. I also highlight unanswered questions and future challenges in the study of SAM and meristem regeneration. Finally, I put forward a model describing stochastic events mediated by epigenetic factors to explain how the gene regulatory network might be initiated at the onset of shoot regeneration. Expected final online publication date for the Annual Review of Genetics, Volume 55 is November 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Leor Eshed Williams
- The Robert H. Smith Institute of Plant Sciences and Genetics in Agriculture, The Hebrew University of Jerusalem, Rehovot 76100, Israel;
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38
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Luzak V, López-Escobar L, Siegel TN, Figueiredo LM. Cell-to-Cell Heterogeneity in Trypanosomes. Annu Rev Microbiol 2021; 75:107-128. [PMID: 34228491 DOI: 10.1146/annurev-micro-040821-012953] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Recent developments in single-cell and single-molecule techniques have revealed surprising levels of heterogeneity among isogenic cells. These advances have transformed the study of cell-to-cell heterogeneity into a major area of biomedical research, revealing that it can confer essential advantages, such as priming populations of unicellular organisms for future environmental stresses. Protozoan parasites, such as trypanosomes, face multiple and often hostile environments, and to survive, they undergo multiple changes, including changes in morphology, gene expression, and metabolism. But why does only a subset of proliferative cells differentiate to the next life cycle stage? Why do only some bloodstream parasites undergo antigenic switching while others stably express one variant surface glycoprotein? And why do some parasites invade an organ while others remain in the bloodstream? Building on extensive research performed in bacteria, here we suggest that biological noise can contribute to the fitness of eukaryotic pathogens and discuss the importance of cell-to-cell heterogeneity in trypanosome infections. Expected final online publication date for the Annual Review of Microbiology, Volume 75 is October 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Vanessa Luzak
- Division of Experimental Parasitology, Faculty of Veterinary Medicine, Ludwig-Maximilians-Universität München, Munich 82152, Germany.,Biomedical Center, Division of Physiological Chemistry, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich 82152, Germany
| | - Lara López-Escobar
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal;
| | - T Nicolai Siegel
- Division of Experimental Parasitology, Faculty of Veterinary Medicine, Ludwig-Maximilians-Universität München, Munich 82152, Germany.,Biomedical Center, Division of Physiological Chemistry, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich 82152, Germany
| | - Luisa M Figueiredo
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal;
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39
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Kuyyamudi C, Menon SN, Sinha S. Contact-mediated cellular communication supplements positional information to regulate spatial patterning during development. Phys Rev E 2021; 103:062409. [PMID: 34271677 DOI: 10.1103/physreve.103.062409] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 06/02/2021] [Indexed: 12/12/2022]
Abstract
Development in multicellular organisms is marked by a high degree of spatial organization of the cells attaining distinct fates in the embryo. Recent experiments showing that suppression of intercellular interactions can alter the spatial patterns arising during development suggest that cell fates cannot be determined by the exclusive regulation of differential gene expression by morphogen gradients (the conventional view encapsulated in the French flag model). Using a mathematical model that describes the receptor-ligand interaction between cells in close physical proximity, we show that such intercellular signaling can regulate the process of selective gene expression within each cell, allowing information from the cellular neighborhood to influence the process by which the thresholds of morphogen concentration that dictate cell fates adaptively emerge. This results in local modulations of the positional cues provided by the global field set up by the morphogen, allowing interaction-mediated self-organized pattern formation to complement boundary-organized mechanisms in the context of development.
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Affiliation(s)
- Chandrashekar Kuyyamudi
- The Institute of Mathematical Sciences, CIT Campus, Taramani, Chennai 600113, India.,Homi Bhabha National Institute, Anushaktinagar, Mumbai 400 094, India
| | - Shakti N Menon
- The Institute of Mathematical Sciences, CIT Campus, Taramani, Chennai 600113, India
| | - Sitabhra Sinha
- The Institute of Mathematical Sciences, CIT Campus, Taramani, Chennai 600113, India.,Homi Bhabha National Institute, Anushaktinagar, Mumbai 400 094, India
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40
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Reassembling gastrulation. Dev Biol 2021; 474:71-81. [DOI: 10.1016/j.ydbio.2020.12.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 12/11/2020] [Accepted: 12/13/2020] [Indexed: 12/18/2022]
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41
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Tuazon FB, Wang X, Andrade JL, Umulis D, Mullins MC. Proteolytic Restriction of Chordin Range Underlies BMP Gradient Formation. Cell Rep 2021; 32:108039. [PMID: 32814043 PMCID: PMC7731995 DOI: 10.1016/j.celrep.2020.108039] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 04/22/2020] [Accepted: 07/24/2020] [Indexed: 12/12/2022] Open
Abstract
A fundamental question in developmental biology is how morphogens, such as bone morphogenetic protein (BMP), form precise signaling gradients to impart positional and functional identity to the cells of the early embryo. We combine rigorous mutant analyses with quantitative immunofluorescence to determine that the proteases Bmp1a and Tolloid spatially restrict the BMP antagonist Chordin in dorsoventral (DV) axial patterning of the early zebrafish gastrula. We show that maternally deposited Bmp1a plays an unexpected and non-redundant role in establishing the BMP signaling gradient, while the Bmp1a/Tolloid antagonist Sizzled is surprisingly dispensable. Combining computational modeling and in vivo analyses with an immobile Chordin construct, we demonstrate that long-range Chordin diffusion is not necessary for BMP gradient formation and DV patterning. Our data do not support a counter-gradient of Chordin and instead favor a Chordin sink, established by Bmp1a and Tolloid, as the primary mechanism that drives BMP gradient formation. The BMP morphogen generates a precise signaling gradient during axial patterning. In the zebrafish embryo, Tuazon et al. find that proteases Bmp1a/Tolloid are key to this process, preventing the long-range diffusion of the BMP antagonist, Chordin. By regionally restricting Chordin, Bmp1a/Tolloid establish the signaling sink that drives BMP gradient formation.
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Affiliation(s)
- Francesca B Tuazon
- Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Xu Wang
- Department of Agriculture and Biological Engineering, Purdue University, West Lafayette, IN 47907, USA; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA
| | - Jonathan Lee Andrade
- Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - David Umulis
- Department of Agriculture and Biological Engineering, Purdue University, West Lafayette, IN 47907, USA; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA.
| | - Mary C Mullins
- Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
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42
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Xi X, Hu Z, Nie X, Meng M, Xu H, Li J. Cross Inhibition of MPK10 and WRKY10 Participating in the Growth of Endosperm in Arabidopsis thaliana. FRONTIERS IN PLANT SCIENCE 2021; 12:640346. [PMID: 33897728 PMCID: PMC8062763 DOI: 10.3389/fpls.2021.640346] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 03/08/2021] [Indexed: 05/26/2023]
Abstract
The product of double fertilization produces seed, which contains three components: triploid endosperm, diploid embryo, and maternal seed coat. Amongst them, the endosperm plays a crucial role in coordinating seed growth. Mitogen-activated protein kinase (MAPK) cascades are conserved in eukaryotes and involved in signal transduction of plant development. MPK3, MPK6, and MPK10 form a small group of MPKs family in Arabidopsis thaliana. MPK3 and MPK6 are extensively studied and were found to be involved in diverse processes including plant reproduction. However, less is known about the function of MPK10. Here, we found WRKY10/MINI3, a member of HAIKU (IKU) pathway engaging in endosperm development, and MPK10 is high-specifically expressed in the early developmental endosperm but with opposite gradients. We further proved that MPK10 and WRKY10 cross-inhibit the expression of each other. The inhibition effect of MPK10 on gene expression of WRKY10 and the downstream targets is supported by the fact that MPK10 interacts with WRKY10 and suppresses the transcriptional activity of WRKY10. Constantly, mpk10 mutants produce big seeds while WRKY10/MINI3 positively regulate seed growth. Altogether, our data provides a model of WRKY10 and MPK10 regulating endosperm development with a unique cross inhibitory mechanism.
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Affiliation(s)
- Xiaoyuan Xi
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Zhengdao Hu
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Xuerui Nie
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Mingming Meng
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Hao Xu
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Jing Li
- College of Tropical Crops, Hainan University, Haikou, China
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43
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Stapornwongkul KS, Vincent JP. Generation of extracellular morphogen gradients: the case for diffusion. Nat Rev Genet 2021; 22:393-411. [PMID: 33767424 DOI: 10.1038/s41576-021-00342-y] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/23/2021] [Indexed: 02/07/2023]
Abstract
Cells within developing tissues rely on morphogens to assess positional information. Passive diffusion is the most parsimonious transport model for long-range morphogen gradient formation but does not, on its own, readily explain scaling, robustness and planar transport. Here, we argue that diffusion is sufficient to ensure robust morphogen gradient formation in a variety of tissues if the interactions between morphogens and their extracellular binders are considered. A current challenge is to assess how the affinity for extracellular binders, as well as other biophysical and cell biological parameters, determines gradient dynamics and shape in a diffusion-based transport system. Technological advances in genome editing, tissue engineering, live imaging and in vivo biophysics are now facilitating measurement of these parameters, paving the way for mathematical modelling and a quantitative understanding of morphogen gradient formation and modulation.
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44
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McKenna KZ, Wagner GP, Cooper KL. A developmental perspective of homology and evolutionary novelty. Curr Top Dev Biol 2021; 141:1-38. [PMID: 33602485 DOI: 10.1016/bs.ctdb.2020.12.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
The development and evolution of multicellular body plans is complex. Many distinct organs and body parts must be reproduced at each generation, and those that are traceable over long time scales are considered homologous. Among the most pressing and least understood phenomena in evolutionary biology is the mode by which new homologs, or "novelties" are introduced to the body plan and whether the developmental changes associated with such evolution deserve special treatment. In this chapter, we address the concepts of homology and evolutionary novelty through the lens of development. We present a series of case studies, within insects and vertebrates, from which we propose a developmental model of multicellular organ identity. With this model in hand, we make predictions regarding the developmental evolution of body plans and highlight the need for more integrative analysis of developing systems.
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Affiliation(s)
- Kenneth Z McKenna
- Division of Biological Sciences, University of California San Diego, La Jolla, CA, United States
| | - Günter P Wagner
- Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT, United States.
| | - Kimberly L Cooper
- Division of Biological Sciences, University of California San Diego, La Jolla, CA, United States
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45
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Greenfeld H, Lin J, Mullins MC. The BMP signaling gradient is interpreted through concentration thresholds in dorsal-ventral axial patterning. PLoS Biol 2021; 19:e3001059. [PMID: 33481775 PMCID: PMC7857602 DOI: 10.1371/journal.pbio.3001059] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 02/03/2021] [Accepted: 01/07/2021] [Indexed: 12/24/2022] Open
Abstract
Bone Morphogenetic Protein (BMP) patterns the dorsal–ventral (DV) embryonic axis in all vertebrates, but it is unknown how cells along the DV axis interpret and translate the gradient of BMP signaling into differential gene activation that will give rise to distinct cell fates. To determine the mechanism of BMP morphogen interpretation in the zebrafish gastrula, we identified 57 genes that are directly activated by BMP signaling. By using Seurat analysis of single-cell RNA sequencing (scRNA-seq) data, we found that these genes are expressed in at least 3 distinct DV domains of the embryo. We distinguished between 3 models of BMP signal interpretation in which cells activate distinct gene expression through interpretation of thresholds of (1) the BMP signaling gradient slope; (2) the BMP signal duration; or (3) the level of BMP signal activation. We tested these 3 models using quantitative measurements of phosphorylated Smad5 (pSmad5) and by examining the spatial relationship between BMP signaling and activation of different target genes at single-cell resolution across the embryo. We found that BMP signaling gradient slope or BMP exposure duration did not account for the differential target gene expression domains. Instead, we show that cells respond to 3 distinct levels of BMP signaling activity to activate and position target gene expression. Together, we demonstrate that distinct pSmad5 threshold levels activate spatially distinct target genes to pattern the DV axis. This study tested three models of how a BMP morphogen gradient is translated into differential gene activation that specifies distinct cell fates, finding that BMP signal concentration thresholds, not gradient shape or signal duration, position three distinct gene activation domains.
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Affiliation(s)
- Hannah Greenfeld
- Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States of America
| | - Jerome Lin
- Institute for Biomedical Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States of America
| | - Mary C. Mullins
- Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States of America
- * E-mail:
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46
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Sasai N, Kadoya M, Ong Lee Chen A. Neural induction: Historical views and application to pluripotent stem cells. Dev Growth Differ 2021; 63:26-37. [PMID: 33289091 DOI: 10.1111/dgd.12703] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Revised: 10/22/2020] [Accepted: 11/02/2020] [Indexed: 12/20/2022]
Abstract
Embryonic stem (ES) cells are a useful experimental material to recapitulate the differentiation steps of early embryos, which are usually invisible and inaccessible from outside of the body, especially in mammals. ES cells have greatly facilitated the analyses of gene expression profiles and cell characteristics. In addition, understanding the mechanisms during neural differentiation is important for clinical purposes, such as developing new therapeutic methods or regenerative medicine. As neurons have very limited regenerative ability, neurodegenerative diseases are usually intractable, and patients suffer from the disease throughout their lifetimes. The functional cells generated from ES cells in vitro could replace degenerative areas by transplantation. In this review, we will first demonstrate the historical views and widely accepted concepts regarding the molecular mechanisms of neural induction and positional information to produce the specific types of neurons in model animals. Next, we will describe how these concepts have recently been applied to the research in the establishment of the methodology of neural differentiation from mammalian ES cells. Finally, we will focus on examples of the applications of differentiation systems to clinical purposes. Overall, the discussion will focus on how historical developmental studies are applied to state-of-the-art stem cell research.
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Affiliation(s)
- Noriaki Sasai
- Developmental Biomedical Science, Nara Institute of Science and Technology, Ikoma, Japan
| | - Minori Kadoya
- Developmental Biomedical Science, Nara Institute of Science and Technology, Ikoma, Japan
| | - Agnes Ong Lee Chen
- Developmental Biomedical Science, Nara Institute of Science and Technology, Ikoma, Japan
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47
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Hamid OA, Eltaher HM, Sottile V, Yang J. 3D bioprinting of a stem cell-laden, multi-material tubular composite: An approach for spinal cord repair. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2021; 120:111707. [DOI: 10.1016/j.msec.2020.111707] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 09/14/2020] [Accepted: 11/03/2020] [Indexed: 01/16/2023]
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48
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Heise K, Kontturi E, Allahverdiyeva Y, Tammelin T, Linder MB, Nonappa, Ikkala O. Nanocellulose: Recent Fundamental Advances and Emerging Biological and Biomimicking Applications. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2021; 33:e2004349. [PMID: 33289188 PMCID: PMC11468234 DOI: 10.1002/adma.202004349] [Citation(s) in RCA: 148] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 08/01/2020] [Indexed: 06/12/2023]
Abstract
In the effort toward sustainable advanced functional materials, nanocelluloses have attracted extensive recent attention. Nanocelluloses range from rod-like highly crystalline cellulose nanocrystals to longer and more entangled cellulose nanofibers, earlier denoted also as microfibrillated celluloses and bacterial cellulose. In recent years, they have spurred research toward a wide range of applications, ranging from nanocomposites, viscosity modifiers, films, barrier layers, fibers, structural color, gels, aerogels and foams, and energy applications, until filtering membranes, to name a few. Still, nanocelluloses continue to show surprisingly high challenges to master their interactions and tailorability to allow well-controlled assemblies for functional materials. Rather than trying to review the already extensive nanocellulose literature at large, here selected aspects of the recent progress are the focus. Water interactions, which are central for processing for the functional properties, are discussed first. Then advanced hybrid gels toward (multi)stimuli responses, shape-memory materials, self-healing, adhesion and gluing, biological scaffolding, and forensic applications are discussed. Finally, composite fibers are discussed, as well as nanocellulose as a strategy for improvement of photosynthesis-based chemicals production. In summary, selected perspectives toward new directions for sustainable high-tech functional materials science based on nanocelluloses are described.
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Affiliation(s)
- Katja Heise
- Department of Bioproducts and BiosystemsAalto UniversityEspooFI‐00076Finland
- Center of Excellence in Molecular Engineering of Biosynthetic Hybrid Materials ResearchAalto UniversityFI‐00076Finland
| | - Eero Kontturi
- Department of Bioproducts and BiosystemsAalto UniversityEspooFI‐00076Finland
| | - Yagut Allahverdiyeva
- Molecular Plant BiologyDepartment of BiochemistryUniversity of TurkuTurkuFI‐20014Finland
| | - Tekla Tammelin
- VTT Technical Research Centre of Finland LtdVTT, PO Box 1000FIN‐02044EspooFinland
| | - Markus B. Linder
- Department of Bioproducts and BiosystemsAalto UniversityEspooFI‐00076Finland
- Center of Excellence in Molecular Engineering of Biosynthetic Hybrid Materials ResearchAalto UniversityFI‐00076Finland
| | - Nonappa
- Department of Bioproducts and BiosystemsAalto UniversityEspooFI‐00076Finland
- Center of Excellence in Molecular Engineering of Biosynthetic Hybrid Materials ResearchAalto UniversityFI‐00076Finland
- Department of Applied PhysicsAalto UniversityEspooFI‐00076Finland
- Faculty of Engineering and Natural SciencesTampere UniversityP.O. Box 541TampereFI‐33101Finland
| | - Olli Ikkala
- Department of Bioproducts and BiosystemsAalto UniversityEspooFI‐00076Finland
- Center of Excellence in Molecular Engineering of Biosynthetic Hybrid Materials ResearchAalto UniversityFI‐00076Finland
- Department of Applied PhysicsAalto UniversityEspooFI‐00076Finland
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49
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Abstract
Members of the Hedgehog family of morphogens mediate the intercellular communication necessary for the organisation and development of many animal tissues. They are modified by various lipid adducts, rendering them insoluble in hydrophilic environments and leading to the contentious question of how these molecules travel in the aqueous extracellular space. Seminal work carried out by Suzanne Eaton and her colleagues has shed light on how these morphogens can spread over long distances through their association with lipoprotein particles. In this Spotlight article, we discuss Suzanne's pioneering work and her contribution to our understanding of the transport and activity of morphogens, in particular Hedgehog. We also describe two other essential aspects of her work: the discovery and characterisation of endogenously present Hedgehog variants, as well as her proposition that, in addition to its role as a morphogen, Hedgehog acts as an endocrine hormone.
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Affiliation(s)
- Elodie Prince
- Université Côte d'Azur, CNRS, INSERM, iBV, Parc Valrose, 06108 Nice Cedex 2, France
| | - Julien Marcetteau
- Université Côte d'Azur, CNRS, INSERM, iBV, Parc Valrose, 06108 Nice Cedex 2, France
| | - Pascal P Thérond
- Université Côte d'Azur, CNRS, INSERM, iBV, Parc Valrose, 06108 Nice Cedex 2, France
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50
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Yang S, Pieters PA, Joesaar A, Bögels BWA, Brouwers R, Myrgorodska I, Mann S, de Greef TFA. Light-Activated Signaling in DNA-Encoded Sender-Receiver Architectures. ACS NANO 2020; 14:15992-16002. [PMID: 33078948 PMCID: PMC7690052 DOI: 10.1021/acsnano.0c07537] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 10/14/2020] [Indexed: 05/22/2023]
Abstract
Collective decision making by living cells is facilitated by exchange of diffusible signals where sender cells release a chemical signal that is interpreted by receiver cells. A variety of nonliving artificial cell models have been developed in recent years that mimic various aspects of diffusion-based intercellular communication. However, localized secretion of diffusive signals from individual protocells, which is critical for mimicking biological sender-receiver systems, has remained challenging to control precisely. Here, we engineer light-responsive, DNA-encoded sender-receiver architectures, where protein-polymer microcapsules act as cell mimics and molecular communication occurs through diffusive DNA signals. We prepare spatial distributions of sender and receiver protocells using a microfluidic trapping array and set up a signaling gradient from a single sender cell using light, which activates surrounding receivers through DNA strand displacement. Our systematic analysis reveals how the effective signal range of a single sender is determined by various factors including the density and permeability of receivers, extracellular signal degradation, signal consumption, and catalytic regeneration. In addition, we construct a three-population configuration where two sender cells are embedded in a dense array of receivers that implement Boolean logic and investigate spatial integration of nonidentical input cues. The results offer a means for studying diffusion-based sender-receiver topologies and present a strategy to achieve the congruence of reaction-diffusion and positional information in chemical communication systems that have the potential to reconstitute collective cellular patterns.
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Affiliation(s)
- Shuo Yang
- Laboratory
of Chemical Biology, Department of Biomedical Engineering, Computational
Biology Group, Department of Biomedical Engineering and Institute
for Complex Molecular Systems, Eindhoven
University of Technology, P.O. Box 513, Eindhoven 5600 MB, The
Netherlands
| | - Pascal A. Pieters
- Laboratory
of Chemical Biology, Department of Biomedical Engineering, Computational
Biology Group, Department of Biomedical Engineering and Institute
for Complex Molecular Systems, Eindhoven
University of Technology, P.O. Box 513, Eindhoven 5600 MB, The
Netherlands
| | - Alex Joesaar
- Laboratory
of Chemical Biology, Department of Biomedical Engineering, Computational
Biology Group, Department of Biomedical Engineering and Institute
for Complex Molecular Systems, Eindhoven
University of Technology, P.O. Box 513, Eindhoven 5600 MB, The
Netherlands
| | - Bas W. A. Bögels
- Laboratory
of Chemical Biology, Department of Biomedical Engineering, Computational
Biology Group, Department of Biomedical Engineering and Institute
for Complex Molecular Systems, Eindhoven
University of Technology, P.O. Box 513, Eindhoven 5600 MB, The
Netherlands
| | - Rens Brouwers
- Laboratory
of Chemical Biology, Department of Biomedical Engineering, Computational
Biology Group, Department of Biomedical Engineering and Institute
for Complex Molecular Systems, Eindhoven
University of Technology, P.O. Box 513, Eindhoven 5600 MB, The
Netherlands
| | - Iuliia Myrgorodska
- Centre
for Protolife Research and Max Planck Bristol Centre for Minimal Biology,
School of Chemistry, University of Bristol, Bristol BS8 1TS, United Kingdom
| | - Stephen Mann
- Centre
for Protolife Research and Max Planck Bristol Centre for Minimal Biology,
School of Chemistry, University of Bristol, Bristol BS8 1TS, United Kingdom
| | - Tom F. A. de Greef
- Laboratory
of Chemical Biology, Department of Biomedical Engineering, Computational
Biology Group, Department of Biomedical Engineering and Institute
for Complex Molecular Systems, Eindhoven
University of Technology, P.O. Box 513, Eindhoven 5600 MB, The
Netherlands
- Institute
for Molecules and Materials, Radboud University, Heyendaalseweg 135, Nijmegen 6525 MB, The Netherlands
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