Attempts to create organs in vitro started with one of the first dissociation-reaggregation experiments where Henry Van Peters Wilson demonstrated that mechanically dissociated sponge cells can reaggregate and self-organize to generate a whole organism. In the subsequent decades, multiple labs were able to generate different types of organs in vitro through the dissociation and reaggregation of organ tissues obtained from amphibians and embryonic chicks. The formation of first tissue-like colonies in vitro was observed for the first time by co-culturing keratinocytes and 3T3 fibroblasts. The phenomena of mechanically dissociated cells aggregating and reorganizing to reform the tissue they were obtained from subsequently led to the development of the differential adhesion hypothesis by Malcolm Steinberg. With the advent of the field of stem cell biology, the potential of stem cells to form organs in vitro was realized early on with the observation that when stem cells form teratomas or embryoid bodies, the differentiated cells can organize into different structures resembling those found in multiple tissue types. The advent of the field of organoids, started with a shift from culturing and differentiating stem cells in two dimensional (2D) media, to three dimensional (3D) media to allow for the development of the complex 3-dimensional structures of organs. Utilization of 3D media culture media methods for the structural organization was made possible with the development of extracellular matrices (ECM). In the late 1980s, Bissell and colleagues showed that a laminin rich gel can be used as a basement membrane for differentiation and morphogenesis in cell cultures of mammary epithelial cells. Since 1987, researchers have devised different methods for 3D culturing, and were able to utilize different types of stem cells to generate organoids resembling a multitude of organs. In the 1990s, in addition to their role in physical support, the role of ECM components in gene expression by their interaction with integrin-based focal adhesion pathways was reported. In 2006, Yaakov Nahmias and David Odde showed the self-assembly of vascular liver organoid maintained for over 50 days in vitro. In 2008, Yoshiki Sasai and his team at RIKEN institute demonstrated that stem cells can be coaxed into balls of neural cells that self-organize into distinctive layers. In 2009 the Laboratory of Hans Clevers at Hubrecht Institute and University Medical Center Utrecht, Netherlands, showed that single LGR5-expressing intestinal stem cells self-organize to crypt-villus structures in vitro without necessity of a mesenchymal niche, making them the first organoids. In 2010, Mathieu Unbekandt & Jamie A. Davies demonstrated the production of renal organoids from murine fetus-derived renogenic stem cells. In 2014, Qun Wang and co-workers engineered collagen-I and laminin based gels and synthetic foam biomaterials for the culture and delivery of intestinal organoids and encapsulated DNA-functionalized gold nanoparticles into intestinal organoids to form an intestinal Trojan horse for drug delivery and gene therapy. Subsequent reports showed significant physiological function of these organoids in vitro and in vivo.
Other significant early advancements included in 2013, Madeline Lancaster at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences established a protocol starting from pluripotent stem cells to generate cerebral organoids that mimic the developing human brain's cellular organization. Meritxell Huch and Craig Dorrell at Hubrecht Institute and University Medical Center Utrecht demonstrated that single Lgr5+ cells from damaged mouse liver can be clonally expanded as liver organoids in Rspo1-based culture medium over several months. In 2014, Artem Shkumatov et al. at the University of Illinois at Urbana-Champaign demonstrated that cardiovascular organoids can be formed from ES cells through modulation of the substrate stiffness, to which they adhere. Physiological stiffness promoted three-dimensionality of EBs and cardiomyogenic differentiation. In 2015, Takebe et al. demonstrated a generalized method for organ bud formation from diverse tissues by combining pluripotent stem cell-derived tissue-specific progenitors or relevant tissue samples with endothelial cells and mesenchymal stem cells. They suggested that the less mature tissues, or organ buds, generated through the self-organized condensation principle might be the most efficient approach toward the reconstitution of mature organ functions after transplantation, rather than condensates generated from cells of a more advanced stage.