Organoids Unite!


Organoids- mini organs in a dish. Image from Science and Human Blog.
*Note: My apologies in advance to anyone who expected this entry to be about a certain popular 80’s Japanese anime series, or that Michael Bay film series featuring intergalactic mecha-wars.
You crawl into the lab in the morning and head to the tissue culture room to check up on your cells. You had just rolled out of bed 5 minutes prior, pants half on, still drowsy as you’ve yet to get your hands on some morning coffee.
Suddenly, you’re jolted awake.
There’s a brain growing in the dish!
This is precisely what happened in the lab, led by the late Dr. Yoshiki Sasai at the RIKEN center for Developmental Biology, which they reported as a “formation of self-forming, three-dimensional, functional cortical tissues” loaded with neurons that are capable of making basic synaptic networks, published in 20081. This seminal discovery burst open an entirely new field of study involving the generation of organoids- functional, three-dimensional mini-organs in a dish.
How to make an organoid.
Making an organoid begins with embryonic stem cells (ESCs)- cells that are capable of becoming any differentiated cell once given the proper cues to differentiate. So what are these cues? They can be endogenous (i.e.- particular gene expression) and exogenous (i.e.- cytokines) stimulation that elicits a signaling cascade in the cell, which primes them for differentiation. ESC aggregates are dissociated into single cells, and placed into small, individual low-adhesion wells where they are allowed to divide while floating. Factors, such as recombinant proteins, cytokines, and gene-carrying vectors are then provided to the wells to serve as the cues to differentiate into the organoid of choice. In Sasai’s landmark paper, a finely-tuned cocktail of recombinant proteins, growth factors, and other media additives led to a 65-75% success rate for cortical organoid generation. With the generation of some organoids, compounds like Matrigel® are also included in the mix to provide a scaffold for the organoid to grow onto, then subsequently placed into bioreactors where the tissue is constantly exposed to fresh media while floating.
The advent of induced pluripotent stem cell (iPSC) technology, developed in the lab of Dr. Shinya Yamanaka, and Dr. Sasai’s work led to an “organoid-boom” of sorts since the 2008 discovery. There is now a collection of reported organoids resembling breast, cerebral cortex, intestine, kidney, liver, lung, optic cup, pituitary gland, prostate, pancreas, and stomach2. Of course, the novelty of creating little organs floating in a dish is pretty cool, but organoids have served as an invaluable resource for biomedical research. They have been used as a multi-dimensional therapeutic platform to study drug delivery and efficacy- something that was previously achievable only through the use of in vivo animal models. Organoids for disease models have also been developed- by taking stem cells from donors with disorders such as ALS and Alzheimer’s, researchers have been able to generate cerebral organoids to try and understand disease etiology3 (see image). Additionally, some organoids have been shown to be implantable back into animal hosts, blending with the native organ to form functional cells. One group successfully xenografted iPS-derived human intestinal organoids into mice, which successfully engrafted to form functional secretory cells4. Current work is underway to harness this technology into autologous transplant-based therapeutics for intestinal diseases, diabetes, liver disease, and macular degeneration among many others.
Cerebral organoid derived from ALS patient stem cells.
Image from USC Stem Cell.
Organoid-based research and therapy still faces numerous challenges. Although they provide a multi-dimensional platform to study drug delivery, they still lack essential in vivo components that can’t be replicated in organoids alone, including the effects of tissue microenvironment and the immune system. Understanding organoid interplay with the host immune system is something that needs careful examination. Even iPS cell-derived organs, such as skin, have been documented to be immune rejected by their original hosts upon transplantation5. Additionally, the relatively “immature”, embryonic stage of organoids poses a major risk of them turning into potent malignancies once implanted into recipients.
It might take some time before these little organs can make a big impact in the clinic, but organoids deepen our understanding of cell differentiation, organogenesis, and uncover challenges in stem cell technology that opens up new avenues for research. But who knows? Perhaps one day, growing your own little organs for therapy might be an option! What do you think about growing a piece of mini-you in a dish? Do you already work with organoids? Let us know at tech@biolegend.com!
Spongebob Squarepants. Nickelodeon Studios.
References:
  1. Self-Organized Formation of Polarized Cortical Tissues from ESCs and Its Active Manipulation by Extrinsic Signals
  2. The boom in mini stomachs, brains, breasts, kidneys and more
  3. Eli and Edythe Broad Innovation Awards in Stem Biology and Regenerative Medicine: The Organ-in-a-Dish Challenge
  4. An in vivo model of human small intestine using pluripotent stem cells
  5. Immunogenicity of induced pluripotent stem cells

Contributed by Kenta Yamamoto, PhD.
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