Collection |

Organoid research

Organoids are cell-derived in vitro 3D organ models and allow the study of biological processes, such as cell behaviour, tissue repair and response to drugs or mutations, in an environment that mimics endogenous cell organisation and organ structures. Starting as a major technological breakthrough they are now firmly established as an essential tool in biological research and also have important implications for clinical use. A major advantage is that organoids can be grown from a limited supply of starting material, e.g. biopsies, and used for drug screening to develop individual therapies. They have further shown potential in the modelling of diseases, gene editing and transplantations and not least helped to answer many important biological questions. Efforts are underway to setup cryopreserved biobanks of human organoids as a resource for researchers and clinicians.

Editorial and comment

Organoid technologies offer unique insights into the biological processes of the tissues they mimic and are being developed at a rapid pace. Here, we introduce a Collection of content from across the Nature Journals, outlining recent progress and challenges in the organoid field.

Editorial | | Nature Cell Biology

Current advances in biotechnology open up unprecedented possibilities to transform human tissues into complex, valuable tissue products, such as organoids. Here, we propose consent for governance as a leading paradigm for the derivation, storage and use of complex human tissue products to ensure adjustment to changing ethical requirements.

Comment | | Nature Cell Biology

Advances in stem cell research offer unprecedented insights into human biology and opportunities for clinical translation. They also raise many questions with social and ethical implications.

Editorial | | Nature Cell Biology

Three-dimensional brain organoid models have come into the spotlight as in vitro tools to recapitulate complex features of the brain. Four recent papers now leverage current technologies to generate new flavours of brain organoids and address aspects of brain biology which, to date, have been challenging to explore.

News & Views | | Nature Cell Biology

Organoids are a powerful tool to study both physiological and disease processes. A completely synthetic matrix assembled from exchangeable modular parts has been developed and not only supports proliferation of human intestinal organoids derived from pluripotent embryonic stem cells, but also augments subsequent ad vivo implantation into injured murine colon.

News & Views | | Nature Cell Biology

Difficult questions will be raised as models of the human brain get closer to replicating its functions, explain Nita A. Farahany, Henry T. Greely and 15 colleagues.

Comment | | Nature

Single-cell analyses in cancer are limited by the small biomass of individual cells. In vitro production of 3D organoid structures from single tumour-derived cells generates sufficient biomass for in-depth analyses.

News & Views | | Nature

In an article published recently in Nature Medicine, the authors generate organoid models of liver neoplasia. In doing so, they highlight both the diversity of current organoid methodologies and their application to cancer modeling and therapeutics discovery.

News & Views | | Nature Medicine

Research articles

Some types of colon tumour are considered immunologically cold owing to their limited response to immunotherapy. Here, the authors model metastatic colorectal tumours using compound genetic mouse models and organoid transplantation and find that their immunogenicity is at least partly regulated by TGFβ signalling in the tumour microenvironment. Stromal-derived TGFβ seems to regulate T-cell differentiation and exclude immune infiltration from tumours. Inhibition of TGFβ can effectively reduce the growth of metastatic colorectal cancer, and synergizes with anti-PD1 blockade, suggesting potential combination strategies for more potent immunotherapy for colorectal cancer.

Letter | | Nature

The mechanisms by which interactions between different cell types influence lineage identity and cell maturation during human development are unknown. Barbara Treutlein and colleagues use single-cell RNA-sequencing to analyse the emergence of hepatocytes lineages in a three-dimensional organoid system that is based on the reconstitution of hepatic, stromal and endothelial interactions. They compare their findings in vitro with data they obtain from fetal and adult human livers, and show that hepatocytes from the organoids closely resemble fetal liver cells. Through a chemical screen, they show that the three-dimensional system can be used to explore how signalling pathways influence endothelial network and hepatoblast formation.

Letter | | Nature

Three-dimensional cellular models of the human brain, or organoids, enable the in vitro study of cerebral development and disease, but exactly which cells are generated and how much of the brain's complexity they recreate is undefined. To investigate in depth the nature of cells in human cerebral organoids differentiated from pluripotent stem cells, Paola Arlotta and colleagues carried out droplet-based single-cell expression analysis on cells isolated from over 30 organoids at developmental stages ranging from 3 to 9 months and beyond. They identify a wide diversity of neurons and progenitors and show that the more mature organoids formed dendritic spines as well as electrically active networks, which responded to light stimulation. The authors suggest that organoids may facilitate the study of circuit function using physiological sensory mechanisms. Elsewhere in this issue, Sergiu Paşca and colleagues show that re-assembling ventral and dorsal forebrain spheroids obtained separately in vitro allows the migration of human interneurons and the formation of functional synapses.

Article | | Nature

GABAergic neurons play important roles in brain function and are implicated in numerous psychiatric disorders. They migrate long distances from the ventral to the dorsal forebrain before integrating to cortical circuits. In vitro modelling of GABAergic neuronal differentiation during this interaction would allow us to investigate the cause of human brain disorders associated with defects in neuronal migration, but this has so far been difficult. Sergiu Paşca and colleagues have developed an approach for generating neural three-dimensional spheroids resembling either the ventral or dorsal forebrain. They show that assembling the two types of spheroids separately in vitro allows the saltatory migration of human interneurons into the cortex, as seen in human development, and the formation of functional synapses with the dorsally derived cortical glutamatergic neurons. In this context, they find that interneurons from Timothy syndrome patients exhibit perturbation in migration patterns. Elsewhere in this issue, Paola Arlotta and colleagues carried out single cell expression analysis on cells from human brain organoids to investigate the nature of cells generated by these three-dimensional models.

Article | | Nature

Epithelial organoids are being used in the laboratory to model organ development and function. So far these systems have relied on animal-derived matrices, which can be highly variable and are poorly defined, a problem that also makes them unsuitable for clinical application. Matthias Lutolf and colleagues have now designed modular synthetic hydrogen networks to support the formation of intestinal organoids from mouse and human intestinal stem cells. The authors produced dynamic matrices, initially optimal for intestinal stem cell expansion, which depends on high stiffness, and subsequently become permissive to intestinal differentiation and organoid formation through softening of their mechanical properties.

Letter | | Nature

The only current treatment for cataracts, the leading cause of blindness, is to extract the damaged lens surgically and implant an artificial intraocular lens. The technique has its limitations, so there is great interest in the possibility of a regenerative medicine approach. Two papers published in this issue of Nature report advances that could bring that prospect a little closer. Kang Zhang and colleagues isolate mammalian lens epithelial stem/progenitor cells and show that Pax6 and Bmi1 are required for their renewal. They have also developed a removal procedure for cataract-affected tissue that preserves these cells, and achieved lens regeneration in rabbits, macaques and in human infants with cataracts. In the second paper, Kohji Nishida and colleagues describe a protocol for in vitro generation of a self-formed ectodermal autonomous multi-zone (SEAM) from human induced pluripotent stem cells. The SEAM includes distinct cell lineages from the ocular surface ectoderm, lens, neuro-retina, and retinal pigment epithelium. Previous experiments had focused mainly on obtaining one cell type. These authors show that cells from the SEAM can be expanded to form a functional corneal epithelium when transplanted to an animal model of blindness.

Letter | | Nature

Zika virus infection has been linked to an increase in the number of infants born with microcephaly in Brazil, but direct experimental proof that Zika virus causes birth defects was lacking. Here Alysson Muotri and colleagues show that the Brazilian Zika virus strain can cross the placenta and cause intrauterine growth restriction, including signs of microcephaly, in the SJL strain of mice. They also show that the virus can infect human brain organoids, inducing cell death by apoptosis and disrupting cortical layers.

Letter | | Nature

Tumor organoids derived from the most common subtypes of primary liver cancer recapitulate the histologic and molecular features of the tissues of origin, even after long-term culture. These in vitro models, as well as those for colorectal cancer reported in Crespo et al. in a previous issue, are amenable for drug screening and allow the identification of therapeutic approaches with potential for cancer treatment.

Article | | Nature Medicine

A protocol based on chemical modulation of WNT activity is used to efficiently generate colonic organoids that recapitulate the molecular features of human colon tissue. Colonic organoids generated from induced pluripotent stem cells from patients with familial adenomatous polyposis provide an in vitro platform for disease modeling and preclinical drug testing.

Letter | | Nature Medicine

Organoids formed by combining pluripotent-stem-cell-derived human neural crest cells with pluripotent-stem-cell-derived intestinal tissue show functional interstitial cells of Cajal and undergo waves of contraction; these tissues reveal insights into the molecular defects characterizing Hirschsprung's disease.

Article | | Nature Medicine

Three-dimensional culture systems and organoids for mammary glands are important to understand mammary gland development. Here, the authors identify conditions (including Neuregulin 1 and R-spondin 1) that allow the culture of organoids that are responsive to hormonal stimulation for up to 2.5 months.

Article | Open Access | | Nature Communications

Sensory hair cells from the mammalian inner ear do not regenerate. Here, the authors induce direct hair cell formation from mouse embryonic stem cells using a three-dimensional culture system and observe differentiation of Type I and Type II vestibular hair cells and establishment of synapses with neurons.

Article | Open Access | | Nature Communications

There has been limited success in generating tissues from human induced pluripotent stem cells (hiPSCs). Here, the authors genetically engineer expression of the transcription factor Gata6 in a single isogenic hiPSC population resulting in complex tissue structures that exhibit liver bud-like properties.

Article | Open Access | | Nature Communications

It is difficult to generate functional human anterior pituitary tissues in vitro. Here, Ozone et al. generate human anterior pituitary from embryonic stem cells by recapitulating in vivodevelopment, and demonstrate this tissue secretes hormones and rescues hypopituitarism when grafted into mice.

Article | Open Access | | Nature Communications

Reviews and Perspectives

In this Review, Drost and Clevers discuss the recent advances in organoid models of cancer and how they can be exploited to drive the translation of basic cancer research into novel patient-specific treatment regimens in the clinic.

Review Article | | Nature Reviews Cancer

3D organoids are valuable tools for increasing understanding of disease biology. In this Review, the authors describe how successful application of organoids into urological cancer research can further our understanding of these diseases and provide preclinical cancer models to aid precision medicine.

Review Article | | Nature Reviews Urology

Protocols