Organoids by design

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Abstract

Organoids are multicellular structures that can be derived from adult organs or pluripotent stem cells. Early versions of organoids range from simple epithelial structures to complex, disorganized tissues with large cellular diversity. The current challenge is to engineer cellular complexity into organoids in a controlled manner that results in organized assembly and acquisition of tissue function. These efforts have relied on studies of organ assembly during embryonic development and have resulted in the development of organoids with multilayer tissue complexity and higher-order functions. We discuss how the next generation of organoids can be designed by means of an engineering-based narrative design to control patterning, assembly, morphogenesis, growth, and function.

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Most cited references 32

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Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis.

Minoru Takasato, Pei X Er, Han S Chiu … (2015)

The human kidney contains up to 2 million epithelial nephrons responsible for blood filtration. Regenerating the kidney requires the induction of the more than 20 distinct cell types required for excretion and the regulation of pH, and electrolyte and fluid balance. We have previously described the simultaneous induction of progenitors for both collecting duct and nephrons via the directed differentiation of human pluripotent stem cells. Paradoxically, although both are of intermediate mesoderm in origin, collecting duct and nephrons have distinct temporospatial origins. Here we identify the developmental mechanism regulating the preferential induction of collecting duct versus kidney mesenchyme progenitors. Using this knowledge, we have generated kidney organoids that contain nephrons associated with a collecting duct network surrounded by renal interstitium and endothelial cells. Within these organoids, individual nephrons segment into distal and proximal tubules, early loops of Henle, and glomeruli containing podocytes elaborating foot processes and undergoing vascularization. When transcription profiles of kidney organoids were compared to human fetal tissues, they showed highest congruence with first trimester human kidney. Furthermore, the proximal tubules endocytose dextran and differentially apoptose in response to cisplatin, a nephrotoxicant. Such kidney organoids represent powerful models of the human organ for future applications, including nephrotoxicity screening, disease modelling and as a source of cells for therapy.

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Modelling cancer in microfluidic human organs-on-chips

Alexandra Sontheimer-Phelps, Bryan A. Hassell, Donald E. Ingber (2019)

One of the problems that has slowed the development and approval of new anticancer therapies is the lack of preclinical models that can be used to identify key molecular, cellular and biophysical features of human cancer progression. This is because most in vitro cancer models fail to faithfully recapitulate the local tissue and organ microenvironment in which tumours form, which substantially contributes to the complex pathophysiology of the disease. More complex in vitro cancer models have been developed, including transwell cell cultures, spheroids and organoids grown within flexible extracellular matrix gels, which better mimic normal and cancerous tissue development than cells maintained on conventional 2D substrates. But these models still lack the tissue-tissue interfaces, organ-level structures, fluid flows and mechanical cues that cells experience within living organs, and furthermore, it is difficult to collect samples from the different tissue microcompartments. In this Review, we outline how recent developments in microfluidic cell culture technology have led to the generation of human organs-on-chips (also known as organ chips) that are now being used to model cancer cell behaviour within human-relevant tissue and organ microenvironments in vitro. Organ chips enable experimentalists to vary local cellular, molecular, chemical and biophysical parameters in a controlled manner, both individually and in precise combinations, while analysing how they contribute to human cancer formation and progression and responses to therapy. We also discuss the challenges that must be overcome to ensure that organ chip models meet the needs of cancer researchers, drug developers and clinicians interested in personalized medicine.

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Human blood vessel organoids as a model of diabetic vasculopathy

Reiner A Wimmer, Alexandra Leopoldi, Martin Aichinger … (2019)

The increasing prevalence of diabetes has resulted in a global epidemic1. Diabetes is a major cause of blindness, kidney failure, heart attacks, stroke and amputation of lower limbs. These are often caused by changes in blood vessels, such as the expansion of the basement membrane and a loss of vascular cells2-4. Diabetes also impairs the functions of endothelial cells5 and disturbs the communication between endothelial cells and pericytes6. How dysfunction of endothelial cells and/or pericytes leads to diabetic vasculopathy remains largely unknown. Here we report the development of self-organizing three-dimensional human blood vessel organoids from pluripotent stem cells. These human blood vessel organoids contain endothelial cells and pericytes that self-assemble into capillary networks that are enveloped by a basement membrane. Human blood vessel organoids transplanted into mice form a stable, perfused vascular tree, including arteries, arterioles and venules. Exposure of blood vessel organoids to hyperglycaemia and inflammatory cytokines in vitro induces thickening of the vascular basement membrane. Human blood vessels, exposed in vivo to a diabetic milieu in mice, also mimic the microvascular changes found in patients with diabetes. DLL4 and NOTCH3 were identified as key drivers of diabetic vasculopathy in human blood vessels. Therefore, organoids derived from human stem cells faithfully recapitulate the structure and function of human blood vessels and are amenable systems for modelling and identifying the regulators of diabetic vasculopathy, a disease that affects hundreds of millions of patients worldwide.