Tissue Engineering: Building a better model of the retina
A lot of what is known about human cells has come from studying cultures that have been grown in a dish. However, these two-dimensional cultures do not accurately represent the native environment in which our cells grow. Over the past decade both bioengineers and stem cell biologists have created three-dimensional cell cultures that promise to provide a more reliable model for studying human tissue. Bioengineers, for example, have been creating ‘organ-on-a-chip’ devices that precisely control the various cues that act on cells (Huh et al., 2010; Zhang et al., 2016). Using these devices, bioengineers have been able to reproduce the three-dimensional environments of certain tissues, including heart and lung tissues, in a way that captures some aspects of how these organs work (Zhang et al., 2018).
Stem cell biologists, on the other hand, have relied on the inherent ability of stem cells to undergo differentiation in a three-dimensional environment, and to create cell masses called organoids that exhibit some complexity of native organs, including the brain (Lancaster et al., 2013; Lancaster and Knoblich, 2014) and kidney (Phipson et al., 2019). There is no doubt that organoids provide a more faithful representation of native tissue than organ-on-a-chip devices, which typically contain at most two to three different cell types. However, organoids exhibit a lot of variability and this, along with their small size, means they cannot easily be used to study how an organ may respond to different drugs. Although organ-on-a-chip devices are generally considered to be less biologically representative, they do offer a more controlled environment for studying the effects of drugs. Therefore, the natural way forward for both these fields would be to combine the advantages of organoids and organ-on-a-chip devices in a single system (Takebe et al., 2017).
Human vision is particularly difficult to study using animal models, since the fundamental characteristics of how we see are different to most animals. This has motivated researchers to use models of the human retina that have been explanted post-mortem, but these can display a lot of donor-donor variability and various disease-related conditions. Recently, researchers have used pluripotent stem cells to generate an organoid of the human retina that has a similar structure to the real thing (Zhong et al., 2014). However, for these models to accurately represent the in vivo environment of the retina, they must also have a blood supply that provides the retina with nutrients. Now, in eLife, Peter Loskill (Fraunhofer Institute and University of Tübingen), Stefan Liebau (University of Tübingen) and colleagues – including Kevin Achberger, Christopher Probst and Jasmin Haderspeck – report the creation of a retina-on-a chip device that reproduces the vascular supply to the retina in vitro using specially designed micro-channels (Achberger et al., 2019).
To create the device, Achberger et al. combined organoids of the human retina with retinal pigment epithelial (RPE) cells, which form part of the complex environment of the human retina in vivo. Each chip has four compartments designed to hold a single organoid, which sit above a porous membrane that separates the retina from the vasculature-like compartment below (Figure 1): First, RPE cells were seeded onto the membrane, followed by the organoids which had been cultured for 180 days prior to plating to ensure they had reached maturity. This design allows small molecules, nutrients, and proteins from the media in the vascular-like channels to diffuse across the porous membrane where they can be transported from the retinal epithelium into the organoids, similar to how transport occurs in vivo. Secreted factors are then carried away from the retina tissue via the flow of fluids which are confined to the vasculature-like channels below.
This retina-on-a-chip device generated by Achberger et al. is the first tissue model to reproduce the specific layer configuration of seven different cell types in the human retina. The organoids seeded into the device expressed markers of major retinal cells such as ganglion cells, bipolar cells, horizontal cells, amacrine cells, Müller glia and photoreceptors. Notably, Achberger et al. showed that RPE cells directly interacted with the outer segment of photoreceptors in the retinal organoid through phagocytosis. They also observed that cells in the organoid formed specific layers that were similar to how retinal cells are structurally organized in vivo (Figure 1). Achberger et al. also found that these devices could reproduce the visual side-effects of the anti-malaria drug choroquine and the antibiotic gentamicin, indicating that these retina models could be used for drug testing.
The retina is an especially difficult organ to model due to the large number of different cell types involved and its complex structure, so the device created by Achberger et al. is at the very forefront of the organ-on-a-chip field. Further studies should focus on: enhancing the throughput of device production and cell cultivation, automating the plating of cells and measurements taken, and eliminating the use of drug absorbing materials. The new device promises to decrease the reliance on animal models in retinal drug testing and could be used to study the effects of new drugs on human retinas before starting clinical trials. This retina model could therefore have a huge impact on drug discovery and safety testing.
Evaluation of variability in human kidney organoidsNature Methods 16:79–87.https://doi.org/10.1038/s41592-018-0253-2
Synergistic engineering: Organoids meet organs-on-a-chipCell Stem Cell 21:297–300.https://doi.org/10.1016/j.stem.2017.08.016
Advances in organ-on-a-chip engineeringNature Reviews Materials 3:257–278.https://doi.org/10.1038/s41578-018-0034-7
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- Version of Record published: October 4, 2019 (version 1)
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The available treatments for depression have substantial limitations, including low response rates and substantial lag time before a response is achieved. We applied deep brain stimulation (DBS) to the lateral habenula (LHb) of two rat models of depression (Wistar Kyoto rats and lipopolysaccharide-treated rats) and observed an immediate (within seconds to minutes) alleviation of depressive-like symptoms with a high-response rate. Simultaneous functional MRI (fMRI) conducted on the same sets of depressive rats used in behavioral tests revealed DBS-induced activation of multiple regions in afferent and efferent circuitry of the LHb. The activation levels of brain regions connected to the medial LHb (M-LHb) were correlated with the extent of behavioral improvements. Rats with more medial stimulation sites in the LHb exhibited greater antidepressant effects than those with more lateral stimulation sites. These results indicated that the antidromic activation of the limbic system and orthodromic activation of the monoaminergic systems connected to the M-LHb played a critical role in the rapid antidepressant effects of LHb-DBS. This study indicates that M-LHb-DBS might act as a valuable, rapid-acting antidepressant therapeutic strategy for treatment-resistant depression and demonstrates the potential of using fMRI activation of specific brain regions as biomarkers to predict and evaluate antidepressant efficacy.
Social touch constitutes a key component of human social relationships, although in some conditions with social dysfunction, such as autism, it can be perceived as unpleasant. We have previously shown that intranasal administration of oxytocin facilitates the pleasantness of social touch and activation of brain reward and social processing regions, although it is unclear if it influences responses to gentle stroking touch mediated by cutaneous C-touch fibers or pressure touch mediated by other types of fibers. Additionally, it is unclear whether endogenous oxytocin acts via direct entry into the brain or by increased peripheral blood concentrations.
In a randomized controlled design, we compared effects of intranasal (direct entry into the brain and increased peripheral concentrations) and oral (only peripheral increases) oxytocin on behavioral and neural responses to social touch targeting C-touch (gentle-stroking) or other (medium pressure without stroking) cutaneous receptors.
Although both types of touch were perceived as pleasant, intranasal and oral oxytocin equivalently enhanced pleasantness ratings and responses of reward, orbitofrontal cortex, and social processing, superior temporal sulcus, regions only to gentle-stroking not medium pressure touch. Furthermore, increased blood oxytocin concentrations predicted the pleasantness of gentle stroking touch. The specificity of neural effects of oxytocin on C-touch targeted gentle stroking touch were confirmed by time-course extraction and classification analysis.
Increased peripheral concentrations of oxytocin primarily modulate its behavioral and neural responses to gentle social touch mediated by C-touch fibers. Findings have potential implications for using oxytocin therapeutically in conditions where social touch is unpleasant.
Key Technological Projects of Guangdong Province grant 2018B030335001.
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