Cell sources and methods for producing organotypic in vitro human tissue models

CHAPTER

Cell sources and methods for producing organotypic in vitro human tissue models

2 Patrick J. Hayden

MatTek Corporation, Ashland, MA, United States

Introduction The goal of organ-on-a-chip (OoC) technology is to reproduce key human organ systems using miniaturized in vitro cultures that are equivalent to at least the smallest functional unit of each organ (Dehne et al., 2017; Ronaldson-Bouchard and and Vunjak-Novakovic, 2018; Huh et al., 2011). The organ equivalents incorporated into the chips do not necessarily resemble their in vivo counterparts in a visual sense, but will reproduce the essential functions of the organ, and will ideally also incorporate any relevant physical/mechanical features [e.g., threedimensional (3D) extracellular environment/architecture, stretching, contraction, fluid flow, and shear forces] that contribute to organotypic differentiation and organ functions such as breathing, cardiac beating, and blood flow. OoC platforms should also incorporate sensors or features that allow measurement of relevant functional parameters (e.g., compatibility with imaging devices, sensors for measuring real-time conditions, and ports for removal of media/tissues for downstream analysis). A wide variety of OoC platforms have been developed, ranging from systems that incorporate multiple repetitions of a single organ for highthroughput screening applications to systems that incorporate several interacting organs (Fig. 2.1). The ultimate vision for OoC platforms is to create a human-ona-chip device that will replicate all key organ systems and physiologically relevant interactions of the human body (Fig. 2.2). OoC technologies are expected to facilitate the transition from animal-based models to human-based models, provide faster and more predictive human toxicity assessments, and lead to faster development of effective human therapeutics. A requisite for development and widespread use of human OoC technologies is reliable access to human tissues and cells. This chapter provides a detailed survey of human tissue/cell sources and isolation methods, including methods that use induced pluripotent stem cells (iPSCs) currently available to researchers. State-of-the-art culturing devices and techniques that can be applied to OoC Organ on a Chip. DOI: https://doi.org/10.1016/B978-0-12-817202-5.00002-4 © 2020 Elsevier Inc. All rights reserved.

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FIGURE 2.1 (A) OrganoPlate 3-lane microfluidic tissue culture device containing 40 independent microfluidic culture chips. (B) TissUse Multi-Organ-Chip platform containing 4 interacting organ models. (A) (Courtesy MIMETAS); (B) Reproduced with permission from Maschmeyer I., Lorenz A.K., Schimek K., Hasenberg T., Ramme A.P., Hu¨bner J., et al., A four-organ-chip for interconnected long-term co-culture of human intestine, liver, skin and kidney equivalents, Lab Chip 15(12), 2015a, 2688 2699. https://doi. org/10.1039/c5lc00392j.

Human tissue/cell sources and isolation methods

FIGURE 2.2 Human-on-a-chip concept: in vitro platform reproducing all key organ tissues and physiological interactions. (Courtesy TissUse, Gmbh)

systems—such as the use of nanopatterned substrates, tunable elastic substrates, air liquid interface cultures, spheroid/organoid culture techniques, and 3D bioprinting—are also described.

Human tissue/cell sources and isolation methods Continuous (immortal) cell lines Human somatic cells are in general capable of only a limited number (40 60) of cell divisions in culture before they become senescent and lose their ability to divide (Hayflick and Moorhead, 1961). However, immortal somatic cell lines with a capacity for unlimited division potential can be obtained by a number of processes. Genetically mutated cells derived from cancerous tissues are a common source for establishing immortal cell lines. In rare cases, cultured normal (noncancer-derived) cells may spontaneously acquire genetic mutations that provide the ability for unlimited growth. Normal cells may also be transformed into immortalized cells by the introduction of viral oncogenes such as EBV, SV40LT, HPV16 E6/E7, and Ad5 E1A (Honegger, 2001; Freshney, 2016). Induction of telomerase activity by transduction of human Telomerase reverse transcriptase (hTERT) into cells can induce immortal transformation while retaining more normal cell phenotypes than viral-induced transformations (Freshney, 2016). The development of methods for establishing and maintaining continuous cell lines in culture marked a revolutionary advancement in biology. Since the establishment of HeLa cells as the first immortal human cell line in 1952

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(Gey et al., 1952), continuous cell lines have become widely used as indispensable and inexpensive tools for basic biological research, chemical metabolism and toxicity tests, and production of biological compounds such as vaccines, antibodies, and therapeutic proteins. Numerous immortal cell lines derived from a wide variety of tissues are now readily available. Key advantages of immortal cell lines are that they are affordable, well characterized, and easy to culture. However, immortal cell lines generally exhibit significant genotypic and phenotypic abnormalities that may limit their ability to reproduce normal cell behavior and may undergo additional genotypic or phenotypic drift with continued long-term passaging. Furthermore, many continuous cell lines have been misidentified or have become contaminated with mycoplasma or other cell lines over time (Geraghty et al., 2014; Lorsch et al., 2014). Authentication of cell lines is now recommended or required for publication or submission of research results to regulatory authorities (Geraghty et al., 2014). Despite their shortcomings, immortal cell lines remain in widespread use and will continue to be important biological tools that may be suitable or advantageous for specific OoC applications. Table 2.1 presents a list of commonly used immortal human cell lines derived from a variety of organs. These cell lines, as well as others, are also available as authenticated and quality-controlled resources from a number of nonprofit repositories (Table 2.2).

Primary cell cultures and early-passage cell lines with finite lifespan Cells obtained directly from fresh tissue are commonly termed as primary cells. Advancements in the development of defined culture media, culture conditions, and matrix requirements have led to an increasing ability to culture many types of normal (nonimmortal) primary cells. With the exception of hematopoiesis-derived cells, which may be cultured as cell suspensions, most primary cells require attachment to a substrate to survive and proliferate. Adherence-dependent primary cell cultures may be initiated by explanting small pieces of tissue into a culture plate with the appropriate medium and allowing cells to migrate and proliferate as monolayer cultures. Alternate methods of initiating primary adherent cell cultures involve mechanical and/or enzymatic disaggregation of tissue to form a cell suspension, following by plating the suspension at a low density onto cell culture plates or flasks. Coating the culture plate with various forms of extracellular matrix material or the presence of an established feeder cell layer may be required to support culture establishment when using either the explant or disaggregation methods (Honegger, 2001; Freshney, 2016). Primary cultures obtained by seeding cells or explanted tissue fragments directly after isolation from fresh tissue will consist of those cells that are capable of attachment and survival under the culturing conditions (e.g., culture medium and extracellular matrix coating). The primary culture will consist of a mixed

Table 2.1 Commonly used continuous (immortal) human cell lines. Cell type

Origin

Name

Reference

Endothelial Hepatic

Liver Liver

SK HEP-1 HepaRG

Epithelial Epithelial Epithelial Keratinocyte Type I pneumocyte Type II pneumocyte Type II pneumocyte Epithelial Epithelial Epithelial Epithelial Epithelial Epithelial Epithelial Glial

Liver Breast Breast Epidermis Lung

HepG2 MCF-7 ZR-75-1 HaCaT hAELVi

Heffelfinger et al. (1992) Parent et al. (2004), Guillouzo et al. (2007), and Takahashi et al. (2015) Diamond et al. (1980) Brooks et al. (1973) Engel et al. (1978) Boukamp et al. (1988) Kuehn et al. (2016)

Lung

A549

Giard et al. (1973)

Lung

NCI-H441

Brower et al. (1986)

Lung Lung Kidney Ovary Colon Colon Cervix Glioma

Reddel et al. (1988) Fogh and Trempe (1975) Graham et al. (1977) Tsuruo et al. (1986) Fogh et al. (1977) Fogh and Trempe (1975) Gey et al. (1952) Balmforth et al. (1986)

Glial Lymphocytic Myeloid Myeloid Myeloid Myeloid

Brain Blood Blood Blood Blood Blood

BEAS-2B Calu-3 HEK-293 A2780 Caco-2 HT-29 HeLa MOG-GCCM U-251 MG EB-3 K562 HL-60 THP-1 U937

Ponten and Macintyre (1968) Epstein and Barr (1964) Andersson et al. (1979) Olsson et al. (1981) Tsuchiya et al. (1980) Sundström and Nilsson (1976)

Adapted from Freshney, R.I. (2016). Culture of Animal Cells: A Manual of Basic Technique and Specialized Applications (7th ed.). NJ: Wiley-Blackwell, with additions.

Table 2.2 Nonprofit immortal cell line repositories. Institution

Headquarters

Website

ATCC

Manassas, VA, United States Australia, Sydney, Australia, Salisbury, Wiltshire, United Kingdom

www.atcc.org

CellBank ECACC

The Leibniz Institute DSMZ: German Collection of Microorganisms and Cell Cultures GmbH (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH) JCRB Cell Bank

Braunschweig, Germany

Ibaraki City, Osaka, Japan

www.cellbankaustralia. com www.pheculturecollections.org.uk/ collections/ecacc.aspx www.dsmz.de

www.cellbank.nibiohn. go.jp

ATCC, American Type Culture Collection; ECACC, The European Collection of Authenticated Cell Cultures; JCRB, Japanese Collection of Research Bioresources.

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population of cells at various stages of differentiation and, for certain tissue types, tissue-specific stem cells with proliferative potential. Cells that are already committed to terminal differentiation may attach and remain viable but will not proliferate further in culture. The proliferation of tissue-specific stem cells will continue until space in the culture vessel becomes limited, at which point the cells may be harvested and passaged into fresh culture vessels. Cells are typically passaged while still in log-phase growth and before reaching confluence, to avoid loss of proliferative capacity owing to contact inhibition that may occur when the cultures become too densely packed. Adherent cells are generally harvested from culture using enzymatic reagents (trypsin or Accutase) or by manual scraping. Primary cells that have been passaged are thereafter termed primary cell lines. The passaged lines will be enriched in cells that have adapted well to the specific culture conditions and those that retain proliferative capacity, while differentiated/nonproliferative cells will die off. With continued culture and successive passaging, the cell lines will at first continue to adapt and become further enriched in cells with proliferative capacity. However, the cells will eventually exhaust their ability to proliferate and become senescent. If the culture conditions are not specifically tuned to promote only the growth of the desired cell type, the cultures may become overgrown with unwanted cell types such as fibroblasts. Conditions that allow in vitro proliferation of many types of primary human cells [e.g., epithelial cells, stromal cells (fibroblasts, stellate cells, pericytes, astrocytes), and endothelial cells] have been successfully developed. However, certain types of cells from key organ systems (e.g., cardiomyocytes, hepatocytes, neurons, islet cells, and monocytes) can only be maintained for a limited time as primary cultures and do not have significant proliferative capacity in vitro. A number of comprehensive texts on the subject of animal and human cell isolation and cell culture techniques are available (Honegger, 2001; Randell and Fulcher, 2013; Picot, 2005; Mitry and Hughes., 2012). Table 2.3 lists protocols in the literature for the isolation and culture of organ-specific human cell types.

Human tissue sources While protocols for isolation of many organ-specific human cell types have been developed, availability and access to fresh human tissue samples may be a significant limitation for researchers outside of clinical research university or hospital settings. Access to fresh human tissues for research requires informed consent of the tissue donor and institutional review board approval (Pirnay et al., 2015). Even for researchers with access to fresh human tissues, cell isolation protocols require specialized techniques that may be difficult to master and are a time-consuming endeavor that may not be feasible or desirable for many laboratories. As an alternative, a number of vendors offer primary human cells (Table 2.4).

Human tissue/cell sources and isolation methods

Table 2.3 Human organ-specific primary cell isolation protocols. Cell type

Reference

Keratinocytes Melanocytes Breast epithelial cells Oral epithelial cells Olfactory neuroepithelial cells Female reproductive tract epithelium Prostate epithelium Coroid plexus Osteoblasts Chondrocytes Myoblasts Fibroblasts Adipocytes

Randell and Fulcher (2013) and Picot (2005) Picot (2005) and Mitry and Hughes (2012) Randell and Fulcher (2013) Randell and Fulcher (2013) Randell and Fulcher (2013)

Mononuclear phagocytes Peripheral blood natural killer cells Neuronal cells Schwann cells Tracheal/bronchial epithelial cells Alveolar epithelial cells Colon epithelial cells Hepatocytes Kupffer cells Glomerular epithelial cells Renal cortical epithelial cells Parathyroid cells Islets of Langerhans cells Corneal and conjunctiva cells Retinal pigment epithelial cells Fetal gastric epithelial cells

Randell and Fulcher (2013) Randell and Fulcher (2013) Randell and Fulcher (2013) Picot (2005) and Mitry and Hughes (2012) Picot (2005) and Mitry and Hughes (2012) Picot (2005) Picot (2005) and Mitry and Hughes (2012) Picot (2005), Mitry and Hughes (2012), Carswell et al. (2012), Brooks et al. (2017), and Ruiz-Ojeda et al. (2016) Picot (2005) Picot (2005) Picot (2005), Gordon et al. (2013), Peng et al. (2013), and Mains and Patterson (1973) Picot (2005) Randell and Fulcher (2013) and Picot (2005) Picot (2005) and Mitry and Hughes (2012) Picot (2005) Randell and Fulcher (2013), Picot (2005), and Mitry and Hughes (2012) Dixon et al. (2013) and Alabraba et al. (2007) Picot (2005) and Mitry and Hughes (2012) Randell and Fulcher (2013), Picot (2005), Mitry and Hughes (2012), Ichimura et al. (2008), and Valente et al. (2011) Picot (2005) and Mitry and Hughes (2012) Picot (2005) and Mitry and Hughes (2012) Randell and Fulcher (2013) and Picot (2005) Randell and Fulcher, 2013 Picot (2005) and Mitry and Hughes (2012) (Continued)

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Table 2.3 Human organ-specific primary cell isolation protocols. Continued Cell type

Reference

Intestinal crypt and villus cells Ovarian cells Vascular smooth muscle cells Endothelial cells Mesenchymal stem cells Peripheral blood mononuclear cells Dendritic cells Regulatory T-cells

Mitry and Hughes (2012), Chopra et al. (2010), Gjorevski et al. (2016), Tong et al. (2018), and Holmberg et al. (2017) Mitry and Hughes (2012) Mitry and Hughes (2012) Mitry and Hughes (2012) Mitry and Hughes (2012) Mitry and Hughes (2012) Fahrbach et al. (2007) Mitry and Hughes (2012)

Table 2.4 Commercial sources of continuous cell lines and primary human cells. Vendor

Headquarters

Website

AllCells ATCC BioIVT Biopredic International Cell Systems, iXCells Biotechnologies

Emeryville, CA, United States Manassas, VA, United States Westbury, NY, United States Saint Grégoire, France Kirkland, WA, United States San Diego, CA, United States Frederick, MD, United States

www.allcells.com www.atcc.org www.bioivt.com www.biopredic.com www.cell-systems.com www.ixcellsbiotech. com www.lifelinecelltech. com www.lonza.com www.mattek.com www.emdmillipore.com

Lifeline Cell Technology Lonza MatTek Corporation MilliporeSigma Novabiosis PromoCell ScienCell Research Laboratories Sekisui XenoTech, LLC Stemcell Technologies Thermo Fisher Scientific Zen-Bio

Basel, Switzerland Ashland, MA, United States Burlington, MA, United States Morrisville, NC, United States Heidelberg, Germany Carlsbad, CA, United States Kansas City, KS, United States Vancouver, BC, Canada Waltham, MA, United States Durham, NC, United States

ATCC, American Type Culture Collection.

www.novabiosis.com www.promocell.com www.sciencellonline. com www.xenotech.com www.stemcell.com www.thermofisher.com www.zen-bio.com

Methods for producing three-dimensional “organotypic” tissue cultures

Induced pluripotent stem cells A seminal advancement in cell culture and regenerative medicine occurred in 2006 with the development of methods for generating iPSCs from differentiated somatic cells via induced expression of four transcription factors (Takahashi et al., 2007a,b; Yu et al., 2007; Sayed et al., 2016). Because adult cells are used, iPSCs avoid the restrictions and controversy surrounding human embryonic stem cells. Human somatic tissues, fluids, and cell types such as fibroblasts, blood cells, and urine have been used to generate iPSCs. The initial iPSC protocols used retroviral and lentiviral systems to integrate transcription factors into the host genome. Recently developed protocols allow the use of nonintegrating systems, including Sendai virus, episomal reprogramming factors, and microRNAs, to generate iPSCs without integrating the reprograming factors into the genome (Fusaki et al., 2009; Warren et al., 2010). Once generated, iPSCs are theoretically capable of differentiation into any cell type; iPSCs are therefore a valuable source for generation of large numbers of cells that normally do not proliferate in vitro (e.g., cardiomyocytes, hepatocytes, and neuronal cells) (McKernan and Watt, 2013). In addition, iPSCs allow researchers to recreate in vitro models of inherited genetic human diseases and enable the derivation of multiple types of organ models from the same donor (“body-on-a-chip” or “you-on-a-chip” devices). Development of protocols to drive differentiation of iPSCs into various tissue-specific lineages is an area of current intense effort. The growing list of organspecific cell types that have been generated to date from iPSCs includes hepatic, cardiac, neuronal, endothelial (including blood brain barrier), pancreatic, lung, renal, and intestinal cells (Table 2.5). iPSC technology currently requires significant expertise and is a time-consuming process. The science is still developing, and current protocols do not yet reproduce fully differentiated organ-specific cell phenotypes. A growing number of iPSC sources currently exist (McKernan and Watt, 2013; De Sousa et al., 2017; Kim et al., 2017; Ntai et al., 2017). The California Institute for Regenerative Medicine (CIRM) hPSC Repository is the world’s largest, containing iPSCs from over 3000 individuals. The CIRM iPSC lines are produced by nonintegrating episomal reprogramming. Demographic and clinical data are available for a variety of diseases or conditions affecting the brain, heart, lung, liver, and eyes. The Coriell Institute for Medical Research (Camden, NJ, United States) offers dozens of iPSC lines related to Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease, and supplies iPSCs to other repositories. European-based cell banks include the European Bank for Induced Pluripotent Stem Cells (De Sousa et al., 2017), the Human Induced Pluripotent Stem Cell Initiative, and StemBANCC (Table 2.6).

Methods for producing three-dimensional “organotypic” tissue cultures Traditional cell isolation techniques and culture methods for adherence-dependent cells typically involve submersion cultures of cell monolayers on two-dimensional

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Table 2.5 Cell types and disease models developed from induced pluripotent stem cells to date. Tissue type

References

Hepatic

Meier et al. (2017), Yamashita et al. (2018), Matoba et al. (2018), Wang et al. (2017), and Takayama and Mizuguchi (2017) Sallam et al. (2014), Jiang et al. (2016), Kamdar et al. (2015), Tanaka et al. (2015), Talkhabi et al. (2016), Ronaldson-Bouchard et al. (2018), Matsa et al. (2016), and Sharma et al. (2017) Schwartz et al. (2015), Lancaster et al. (2013), Centeno et al. (2018), Lee et al. (2017), Gabriel and Gopalakrishnan (2017), Klaus et al. (2019), Pamies et al. (2017), and Hofrichter et al. (2017) Bao et al. (2015), Wong et al. (2012), Sone and Nakao (2013), Qian et al. (2017), and Stebbins et al. (2016) Kondo et al. (2018a), Loo et al. (2018), Bose and Sudheer (2016), Yabe et al. (2017), and Kim et al. (2016) Wang et al. (2016) and Wilkinson et al. (2018) Sinagoga et al. (2018), Kondo et al. (2018b), Miura and Suzuki (2018), Takahashi et al. (2018), and Rahmani et al. (2019) Takasato and Little (2017) and Schutgens et al. (2019)

Cardiac

Neuronal

Endothelial (including blood brain barrier) Pancreatic Lung Intestinal

Renal

Table 2.6 Repositories and other sources of induced pluripotent stem cells. Institution

Website

American Type Culture Collection Boston University Center for Regenerative Medicine California Institute for Regenerative Medicine Coriell Institute for Medical Research European Bank for Induced Pluripotent Stem Cells Harvard Stem Cell Institute New York Stem Cell Foundation StemBANCC Tempo Bioscience Human Induced Pluripotent Stem Cell Initiative UK Stem Cell Bank US National Institute of Mental Health US National Institute of Neurological Disorders and Stroke

www.atcc.org www.bu.edu/dbin/stemcells/ iPSC_bank.php www.cirm.ca.gov www.coriell.org www.ebisc.org www.hsci.harvard.edu www.nyscf.org www.stembancc.org www.tempobioscience.com www.hipsci.org www.nibsc.org/ukstemcellbank www.nimhgenetics.org www.nindsgenetics.org

Methods for producing three-dimensional “organotypic” tissue cultures

(2D) plastic substrates. These methods were developed to promote proliferation of cells and generally lead to loss of differentiated cellular functions. Moreover, traditional 2D culture environments lack the important cell cell, cell matrix, 3D architecture, and mechanical cues (e.g., stretch, strain, shear forces, nanotopography, and substrate compliance) that are found in the in vivo environment of the cells and that are essential for functional differentiation (Huh et al., 2011; Schmeichel and Bissell, 2003; Alhaque et al., 2018). Recognition of the inherent limitations of 2D culture environments has motivated efforts to develop 3D cell culture conditions that better replicate in vivo tissue architectures and provide more physiologically relevant “organotypic” in vitro tissue models of normal function and disease. A variety of 3D organotypic tissue culture techniques and models have been developed over the past decades. Several of these techniques are used as key building blocks for producing tissues that may be incorporated into OoC platforms described in this book, which add organ connectivity and mechanical features such as medium flow and shear forces. The remainder of this chapter covers current approaches to producing 3D organotypic tissue models. Table 2.7 provides a list of commercial sources of cultureware, devices, and supplies. Table 2.8 lists the current commercial providers of ready-to-use 3D organotypic tissue models.

Use of controlled substrate rigidity and nanopatterned culture substrates to enhance morphological and functional differentiation Functional organotypic differentiation depends on the presence of an appropriately structured microenvironment. The mechanical properties of the matrix, such as elasticity and nanotopography, provide fundamental cues that regulate and guide cell migration, morphology, assembly and alignment, signal transduction pathways, and gene transcription (Kim et al., 2013; Park et al., 2012; Kshitiz et al., 2012). Nanopatterned culture surfaces have been designed to provide a cellular microenvironment that mimics the architecture of the native extracellular matrix. Cells can align, elongate, grow, and migrate along the nanopatterned surfaces, leading to more physiologically representative structural and functional phenotypes. For example, iPSC-derived cardiomyocytes cultured on nanopatterned culture surfaces exhibit polarized expression of gap junction proteins such as Cx43 and develop anisotropic cell shape, striated sarcomeres, and tissue-level alignment, as well as achieving enhanced baseline electrophysiology such as faster longitudinal conduction velocity and lower resting membrane potential (Fig. 2.3; Kim et al., 2010). Nanopatterned culture substrates have also been used to enhance the morphological and functional differentiation of vascular smooth muscle cells (Chaterji et al., 2014), endothelial cells (Jeon et al., 2015), osteocytes (You et al., 2010), and skeletal muscle cells (Smith et al., 2016) in vitro. Traditional tissue culture plasticware is much stiffer than the natural extracellular microenvironments found in tissues and organs. The elastic modulus of

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Table 2.7 Commercial suppliers of culture devices and products for organotypic culture models. Company

Headquarters

Products

Website

Accela, Strašnice Advanced BioMatrix

Czech Republic Carlsbad, CA, United States

www.accela.eu www. advancedbiomatrix. com

Corning

Corning, NY, United States

ExCellness Biotech SA

Lausanne, Switzerland

Greiner Bio-One GmbH

Kremsmünster, Austria

Matrigen Life Technologies MatTek Corporation

Brea, CA, United States Ashland, MA, United States

MilliporeSigma

Burlington, MA, United States

NanoSurface Biomedical

Seattle, WA, United States

Rotary bioreactors Extracellular matrix material, scaffolds, CytoSoft elastic modulus plates, bioinks Cell culture plasticware and reagents, microporous membrane inserts, spheroid-forming plates, attachment plates Elastic substrate cultureware and products Cell culture plasticware and reagents, microporous membrane inserts, spheroid-forming plates Softwell elastic substrate plates Glass-bottomed culture dishes, nanopatterned dishes Cell culture plasticware and reagents, microporous membrane inserts, spheroid-forming plates Nanopatterned dishes

Synthecon

Houston, TX, United States Waltham, MA, United States

ThermoFisherScientific

Rotary bioreactors Cell culture plasticware and reagents, microporous membrane inserts, spheroid-forming plates

www.corning.com/ worldwide/en/ products/lifesciences.html

www.excellness. com www.gbo.com/ en_US.html

www.matrigen. com www.mattek.com

www.emdmillipore. com

www. nanosurfacebio. com www.synthecon. com www.thermofisher. com

Methods for producing three-dimensional “organotypic” tissue cultures

Table 2.8 Commercial suppliers of three-dimensional organotypic culture models. Company

Headquarters

Products

Epithelix

Geneva, Switzerland Schlieren, Switzerland Ashland, MA, United States

Lung epithelial models

InSphero MatTek Corporation Organovo

Phenion Episkin StemoniX

San Diego, CA, United States Düsseldorf, Germany Lyon, France Maple Grove, MN, United States

Liver, pancreas, and cancer spheroid models Skin, lung, corneal, intestinal, vaginal, and oral epithelial models; primary human cells Bioprinted liver and kidney models

Skin models Skin, corneal, and other epithelial models Cardiac and brain spheroid models; two-dimensional brain models

www.epithelix. com www.insphero. com www.mattek. com www.organovo. com www.phenion. com www.episkin. com www.stemonix. com

FIGURE 2.3 Alignment of cardiomyocytes on nanopatterned culture well. (Courtesy NanoSurface Biomedical).

typical cell culture plastic is on the order of 1 3 107 kPa, whereas tissues and organs have much lower values, typically 0.2 64 kPa (Wells, 2008; Charrier et al., 2018). Tissue stiffening has been shown to be a major component of aging and fibrotic diseases (Lampi and Reinhart-King, 2018; Asano et al., 2017;

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Liu et al., 2010). Substrate stiffness has also been found to regulate proliferation and differentiation of stem cells (Engler et al., 2006; Gilbert et al., 2010; Smith et al., 2017) and the growth and migration of cancer cells (Tilghman et al., 2010). Polyacrylamide, polydimethylsiloxane, and silicon substrates can be engineered to match the compliance of the in vivo environments of various organs and disease states (Mih et al., 2011; Smith et al., 2017). Several companies offer cultureware that features physiologically compliant substrates, including Matrigen (www. matrigen.com), Advanced BioMatrix (www.advancedbiomatrix.com), and ExCellness Biotech (www.excellness.com).

Use of microporous membrane substrates to prepare cultures with polarized barrier, transport, and differentiated properties Many epithelial and endothelial tissues exist in vivo as polarized sheets or tubes that are bounded on the basolateral side by a basement membrane and have an external (e.g., skin) or luminal (e.g., airways, intestine, kidney tubules, and blood vessels) side that may be exposed to air or liquid. These types of polarized tissues are commonly modeled in vitro by means of a “raft” culture on metal mesh grids (Anacker and Moody, 2012) or on specialized microporous membrane support wells (Fig. 2.4; Adler et al., 1987; Be´rube´ et al., 2010) to create air liquid interface or liquid liquid interface environments. Tissues cultured under these conditions typically form tight junctions between cells at the apical layers and provide selective barrier function. Morphologically, these cultures may range from flattened or simple cuboidal monolayers to multilayered 3D stratified or pseudostratified epithelial structures. Differentiated organotypic functional

FIGURE 2.4 Schematic illustration of air-liquid interface tissue culture using microporous membrane culture insert. (Courtesy MatTek Corp.)

Methods for producing three-dimensional “organotypic” tissue cultures

FIGURE 2.5 Examples of organotypic air-liquid interface human skin, intestine and airway epithelial tissues. (Courtesy MatTek Corp)

attributes of these models include a stratum corneum for epidermal models (Bell et al., 1981; Asselineau et al., 1985; Cannon et al., 1994), mucus-secreting goblet cells for airway (Bolmarcich et al., 2018) or intestine (Ayehunie et al., 2018), brush border for intestine (Ayehunie et al., 2018), and beating cilia for airway (Be´rube´ et al., 2010). Multiple cell types, such as epithelial, stromal, endothelial, and immune cells, may be incorporated together to produce more complex cocultures with additional in vivo like functionality (Fizes¸an et al., 2019; Marescotti et al., 2019). Fig. 2.5 displays representative examples of epidermal, bronchial, and intestinal epithelial tissue models produced on microporous membrane inserts. These organotypic systems provide isolated apical and basolateral compartments that allow realistic in vivo like drug/environmental exposures and are very useful for studies of drug transport and efficacy (Kaluzhny et al., 2018; Ayehunie et al., 2018), toxicology and safety (Hayden et al., 2015; Gordon et al., 2015; Maschmeyer et al., 2015a,b; Peters et al., 2019; Hoppensack et al., 2014), and viral or bacterial infections (Bai et al., 2015; Maldonado-Contreras et al., 2017). Human diseases such as asthma (Bai et al., 2015; Hackett et al., 2011) and psoriasis (Chamcheu et al., 2015) have also been successfully modeled with these organotypic systems. Recently, membranes fabricated from polydimethylsiloxane were used to add in vivo like mechanical stretching features to air liquid interface systems (Fig. 2.6; Novak et al., 2018; Felder et al., 2019).

Techniques for preparing three-dimensional spheroids/organoids with differentiated organotypic functions A variety of methods have been developed for inducing scaffold-free selfassembly of cells into 3D spheroids or organoids that mimic key structural and functional attributes of the original organ (Alhaque et al., 2018; Sato and

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FIGURE 2.6 (A) Air-liquid interface PDMS Lung-on-Chip epithelial tissue allows dynamic medium and air flow, shear stress and stretching. (B) Air-liquid interface Lung-on-Chip platform containing 12 alveolar epithelial tissues featuring membrane with in vivo-like expansion and contraction. (A) Reproduced with permission from Huh D., Matthews B.D., Mammoto A., Montoya-Zavala M., Hsin H.Y. and Ingber D.E., Reconstituting organ-level lung functions on a chip, Science 328 (5986), 2010, 1662 1668. https://doi.org/10.1126/science.1188302; (B) Courtesy Alveolix.

Clevers, 2015). These methods make use of the hanging drop technique, rotary reactor devices, embedding in hydrogel matrices, or nonadherent plates or molds. Organoid culture techniques have been applied to produce models of the liver (Meier et al., 2017; Lee et al., 2013; Bell et al., 2016; Proctor et al., 2017;

Methods for producing three-dimensional “organotypic” tissue cultures

FIGURE 2.6 (Continued).

Messner et al., 2018), pancreas (Bose and Sudheer, 2016; Kim et al., 2016; Zuellig et al., 2014), brain (Schwartz et al., 2015; Lancaster et al., 2013; Lee et al., 2017; Gabriel and Gopalakrishnan, 2017; Klaus et al., 2019; Pamies et al., 2017; Hofrichter et al., 2017), kidney (Schutgens et al., 2019), heart (Beauchamp

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CHAPTER 2 Cell sources and methods

FIGURE 2.7 A process for producing cerebral organoids from hIPSCs using a spinning bioreactor. Reproduced with permission from Lancaster M.A., Renner M., Martin C.-A., Wenzel D., Bicknell L.S., Hurles M.E., et al., Cerebral organoids model human brain development and microcephaly, Nature 501, 2013, 373 379

et al., 2015; Rismani Yazdi et al., 2015), intestine (Miura and Suzuki, 2018; Takahashi et al., 2018; Rahmani et al., 2019; Sachs et al., 2017; Mu´nera and Wells, 2017), and cancer (Schmeichel and Bissell, 2003; Plummer et al., 2019; Herter et al., 2017). Coculture models of the liver have included hepatocytes, stellate cells, and Kupffer cells and are reported to maintain drug metabolism capabilities long-term and to demonstrate in vivo like inflammatory responses (Lee et al., 2013; Messner et al., 2018). Brain organoids have been constructed with glial cells, pericytes, and astrocytes, and demonstrate extensive neurite outgrowth, electrical connectivity, and myelination (Schwartz et al., 2015; Lancaster et al., 2013; Pamies et al., 2017). The size of organoid structures should be limited to diameters of ,500 nm, the limit of oxygen diffusion, to maintain cell viability and avoid cell necrosis from lack of oxygen. An example of cerebral organoid production from human iPSCs is depicted in Fig. 2.7 (Lancaster et al., 2013).

Three-dimensional bioprinting The application of 3D printing techniques to biological systems has provided unprecedented opportunities to reproduce heterogeneous tissues with a complex 3D architecture (Xia et al., 2018; Kolesky et al., 2018; Vanderburgh et al., 2017). Cells, growth factors, and matrix materials combined together in so-called “bioinks” are deposited layer by layer to produce the 3D structures. Bioprinting has leveraged inkjet, laser-assisted, and extrusion printing techniques; computeraided design files are used to direct the deposition of the cells and biomaterials

Summary/Outlook

with microscale resolution. Bioinks may be synthetic or biologically derived polymers. Common synthetic polymers used in bioink include modified poly(ethylene glycol), poly(lactic acid), poly(lactic-co-glycolic acid), and poly(e-caprolactone). Bioinks prepared from thermosensitive polymers (e.g., Pluronic F127) that can later be liquefied and removed have been used to create vasculature or tubule-like networks within bioprinted tissues (Herter et al., 2017). Biologically derived polymers commonly used in preparing bioinks include collagens, gelatin, hyaluronic acid, fibrin, alginate, and decellularized extracellular matrices (Herter et al., 2017). These polymers are often chemically modified or combined with ceramic, glass, or hydroxyapatite to provide improved mechanical strength and rheological properties. Bioprinting has been achieved and described for both hard tissues such as bone and cartilage (Kolesky et al., 2018; Mu¨ller et al., 2017; Nguyen et al., 2017) and soft tissues such as skin (Xia et al., 2018), liver (Xia et al., 2018; Ma et al., 2016; Norona et al., 2019), kidney (Xia et al., 2018; King et al., 2017; Homan et al., 2016; Homan et al., 2019; Lin et al., 2019), brain (Xia et al., 2018; Espinosa-Hoyos et al., 2018), lung (Xia et al., 2018), heart (Lind et al., 2017), intestine (Madden et al., 2018), and vasculature (Xia et al., 2018; Kolesky et al., 2016; Zhu et al., 2017). Bioprinting processes enable precise placement of multiple cell types and heterologous material components, thereby providing tremendous promise for replicating functional vasculature, tubules, and glands. Remarkable progress has been made in bioprinting, and techniques continue to develop, along with new bioink materials that are both printable and biocompatible. A variety of companies now offer bioprinting devices, bioinks, and related supplies (Table 2.9).

Summary/Outlook The fields of in vitro cell culture and organotypic model development are experiencing an exciting new era brought about by key advancements. Methods for creating immortal cell lines are well established, and methods for isolation and maintenance of primary human cells have been developed for most tissues and organs. A wide variety of immortal and primary human cells are now readily available to the research community. Use of iPSC technology enables largescale generation of differentiated cell types that were not previously available for research because of proliferation limitations. As the methods for culturing of normal human cells and differentiation of organ-specific cells from iPSCs continue to advance, reliance on immortal cell lines will likely decrease. Key advancements in novel culture substrates and scaffold materials, culturing techniques, spheroid/organoid models, and bioprinting are facilitating rapid progress in the development of in vitro models that replicate complex in vivo like structures and multicellular interactions. Major ongoing needs include

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CHAPTER 2 Cell sources and methods

Table 2.9 Commercial suppliers of bioprinter devices, bioinks, and related services and supplies. Company

Headquarters

Website

3D Bioprinting Solutions Advanced Solutions Life Sciences Allevi

Moscow, Russia Louisville, KY, United States Philadelphia, PA, United States Vancouver, BC, Canada

www.bioprinting.ru www.lifesciences. solutions www.allevi3d.com

Aspect Biosystems Cellbricks CELLINK Cyfuse Biomedical K.K. EnvisionTEC nScrypt Poietis regenHU ROKIT Healthcare

Berlin, Germany Gothenburg, Sweden Tokyo, Japan Dearborn, MI, United States Orlando, FL, United States Pessac, France Villaz-Saint-Pierre, Switzerland Seoul, Korea

www.aspectbiosystems. com www.cellbricks.com www.cellink.com www.cyfusebio.com/en www.envisiontec.com www.nscrypt.com www.poietis.com www.regenhu.com www.rokithealthcare.com

improved protocols for differentiating iPSCs to more faithfully recapitulate organ-specific phenotype and functions, and universal culture media (i.e., blood surrogates) that can support multiple cell and organ types. Continued progress in these areas will lead to better organotypic differentiation, more faithful reproduction of in vivo organ function, and physiologically relevant modeling of human disease. OoC platforms and technologies will leverage advancements in cell and organotypic tissue culture to model organ organ interactions by providing organ connectivity, medium flow (artificial blood), and mechanical forces. These combined technologies are expected to greatly advance our understanding of the biology and interactions of human organs and their functions under normal and disease conditions. Organotypic human models in OoC platforms will also enable rapid in vitro assessment of absorption, distribution, metabolism, excretion, and toxicity of chemicals and drugs, thereby facilitating faster and more efficient development of human therapeutics.

References Adler, K.B., Schwartz, J.E., Whitcutt, M.J., Wu, R., 1987. A new chamber system for maintaining differentiated guinea pig respiratory epithelial cells between air and liquid phases. BioTechniques 5, 462 466.

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Further reading Huh, D., Matthews, B.D., Mammoto, A., Montoya-Zavala, M., Hsin, H.Y., Ingber, D.E., 2010. Reconstituting organ-level lung functions on a chip. Science 328 (5986), 1662 1668. Available from: https://doi.org/10.1126/science.1188302. Shi, Y., Inoue, H., Wu, J.C., Yamanaka, S., 2017. Induced pluripotent stem cell technology: a decade of progress. Nat. Rev. Drug Discov. 16 (2), 115 130. Available from: https://doi.org/10.1038/nrd.2016.245.

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