In the modern fast-paced worlds of research and medicine, disease models that take us closer to the real-life situation are highly desirable. While we can’t discredit the power of in vitro cell culture methods to provide important clues about biological processes, mechanisms of disease, and response to drugs, the availability of life-like tissue systems such as organoids provides obvious opportunities to study these aspects of human biology in a much more realistic manner.

What Exactly Is an Organoid?

Organoids are mini 3D versions of organs that are grown in vitro. It is possible to generate organoids from isolated organ progenitors from the organ of interest, or from pluripotent stem cells who’s self-renewal and differentiation properties make it possible to generate organoids that contain virtually any cell type. Advances in 3D cell culture technology aid organoid organization into life-like 3D structures in a similar manner to that which occurs during in vivo organogenesis. Microscopically, organoids are highly similar to the real-life organ that they are developed to mimic.

History

The earliest attempts to generate organoids were reported by a scientist working with sponges in the early 1900’s (1). This study and those that followed over the next many decades were based largely on the mechanical dissociation and reaggregation of cells or tissues from aquatic organisms. When the stem cell biology field emerged in the 1980’s, scientists quickly saw the opportunity to use stem cells to generate organs in vitro, and this was based to a large extent on the observation that stem cells from multi-tissue tumors (teratomas) could organize themselves into distinct structures that mimicked the tissue type they originated from (2).

The modern field of organoid biology started with a shift from culturing and differentiating stem cells in 2D to 3D growth media to permit and encourage the development of the complex 3D structures of organs.

Modern-Day Organoids

Advances in our understanding of mammalian tissue development, tissue homeostasis, and extracellular matrix biology, coupled with parallel advances in stem cell culture and 3D culture technology, have made it possible to generate organoids that serve as realistic in vitro models of mammalian tissue.

To date, organoids that represent a growing list of diverse organs have been generated, including the lung, stomach, pancreas, brain, eye, liver, skin, and many more.

According to Lancaster and Knoblich’s comprehensive review of organoid technologies (2), organoids must fulfill certain criteria:

  • Organoids must encompass multiple cell types corresponding to the target organ.
  • They must be able to perform functions specific to the organ of interest e.g., contraction
  • Cells that make up the organoid must be grouped and spatially organized in a manner that resembles the organ of interest

Table 1: A generalized workflow for organoid development using pluripotent stem cells

1. Isolation of pluripotent stem cells (PSCs)

PSCs are isolated from the species of interest. To date, organoids have been generated successfully from human and mouse PSCs.

2. Differentiation into desired cell types

Here, a combination of relevant growth factors and media compositions is used to coax the cells to commit to a differentiation program that resembles that of the desired organ type.

3. Cell sorting & spatially restricted lineage commitment

These are processes that occur inherently during in vivo organogenesis. Recapitulating these processes requires the support of a 3D culture environment, which usually involves the application of an extracellular matrix gel e.g., Matrigel, a laminin-rich matrix that resembles the in vivo environment to encourage and support a program of organogenesis that mimics the real-life situation.

4. Organoid is ready for diverse applications in research and medicine

So What Can We Do with Organoids?

Since organoid technology took off a decade ago, the literature has become bursting at the seams with new applications for these remarkable life-like miniature organs. While we can’t cover every possible use for organoids in this post, we will try to cover the main areas of interest with a few notable examples.

Research and Drug Development

Embryonic Development

  • Organoids have been used to study prenatal developmental processes and processes involved in tissue maintenance, aspects that are otherwise very difficult, if not impossible, to study in humans.

Disease Models

  • Organoids are used to study a range of diseases including cancer, genetic disorders, autism, diabetes, and microbial infection.
  • The possibility to genetically modify the cells used to generate an organoid makes it feasible to address the physiological consequences of certain genotypes that are otherwise not possible to study in humans. This also creates an opportunity to address the potential of gene-editing techniques to cure certain diseases.
  • Examples of organoids as disease models: Patient-derived organoids have been used to study disease mechanisms and identify personalized treatments for cystic fibrosis. Brain organoids have been instrumental in our understanding of how Zika virus induces microcephaly. Human liver organoids have made it possible to study distinct types of liver cancer, a group of disease that suffers from a lack of translatable in vitro disease models.

Drug and Toxicity Screening

  • Organoids represent important drug screening tools, allowing us to examine the beneficial and detrimental effects of new drugs in a setup that resembles the real-life situation better than cellular screening assays.
  • The possibility to use liver organoids to study drug metabolism may even generate results that are more translatable to humans than animal models.
  • There are fewer ethical obstacles to drug testing in organoids as compared to animal models. As organoid technology advances further, it may also allow for a reduction in the numbers of animals used in disease and drug testing.

Medical Applications

The potential to use organoid technology to boost or replace organs that fail as a result of disease is probably one of the most exciting ambitions within the field. Although organoids are a way off from completely taking the place of real-life human organs (for one, they are too small), advances in the field to date are very promising.

Let’s take the efforts of Takanori Takebe and his group at Yokohama City as an example. The team generated a platform to create liver buds (structures that resemble the liver of a 6-week old human embryo) from human induced pluripotent stem cells. Astonishing effects were observed when only a dozen of these liver buds were transplanted into mouse abdomens. Remarkably, the transplanted buds connected with the animal’s blood supply within just 2 days, and the cells went on to develop into mature liver cells that recapitulated specific liver functions e.g., they produced liver-specific proteins and could metabolize drugs. The team then used a toxic drug to induce liver failure, and while most of the mice in the control group died within a month, the majority of the transplant recipients survived (3).

The Future for Organoids

Organoid technology is likely to bring us closer than ever before to understanding biological processes and diseases in a human context. Clinical trials involving organoids are already taking place. Here, patient-derived organoids are generated to guide personalized treatments. This has been very useful in the treatment of cystic fibrosis and is becoming more and more common in cancer treatment strategies.

With regards to their medical use, employing patient-derived cells to generate organoids would circumvent the major challenges associated with conventional organ transplantation strategies, such as immunocompetency issues and need for immunosuppression, and organ rejection. With advances such as those from Takebe’s group, clinical trials investigating the use of organoids in humans might only be around the corner.

We are certainly very excited about what the future has in store for organoids! What about you?

Literature Cited:

  1. Wilson HV. A NEW METHOD BY WHICH SPONGES MAY BE ARTIFICIALLY REARED. Science. 1907;25(649):912-5.
  2. Lancaster MA, Knoblich JA. Organogenesis in a dish: modeling development and disease using organoid technologies. Science. 2014;345(6194):1247125.
  3. Takebe T, Sekine K, Enomura M, Koike H, Kimura M, Ogaeri T, et al. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature. 2013;499(7459):481-4.

Article by Karen O’Hanlon Cohrt PhD. Contact Karen at karen@tempobioscience.com. 

Karen O’Hanlon Cohrt is a Science Writer with a PhD in biotechnology from Maynooth University, Ireland (2011). After her PhD,  Karen moved to Denmark and held postdoctoral positions in mycology and later in human cell cycle regulation, before moving to the world of drug discovery. Her broad research background provides the technical know-how to support scientists in diverse areas, and this in combination with her passion for writing helps her to keep abreast of exciting research developments as they unfold. Follow Karen on Twitter @KarenOHCohrt. Karen has been a science writer since 2014; you can find her other work on her portfolio.

 

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