Considerations for engineering composable, disease-tunable 3D human microtissues
Life operates in three spatial dimensions (3D), as do the patients for whom we are developing therapies and cures. Earlier limitations in cell culture and analysis methods constrained us to 2D cell culture substrates, but the amount of valuable information we can extract from such systems is quite limited, and largely exhausted.
In this article, we will share some of what we have learned over the past 10 years as pioneers in the 3D cell culture space and provide guidance for those who are just getting started with 3D models and end-point assays.
The human organism is composed of cells, tissues and organs with defined functions and a variable capacity for regeneration. Adult, mature cells perform the bulk of functions while regenerative capacity is mediated either by rare, specialised progenitor cells or adult, differentiated cells that can reactivate regenerative programmes. Primary, differentiated adult cells, isolated from donor material, are therefore the performance gold standard for building 3D models.
Even though not an inexhaustible source, cell stocks lasting months to years can be built up from a single donor for some organ systems as, for example, the liver. An alternative to working directly with adult cells is starting with stem or progenitor cells, such as human pluripotent stem cells-derived progenitors or Lgr5+ cells isolated from adult tissue. This permits for an in vitro expansion, at the cost of often questionable maturity as the degree of heterogeneity among microtissues increases as they grow.
Tissues are heterotypic in nature and composed of multiple different cell types arranged in 3D. While most cell types in solid organs are organ-specific (eg, liver hepatocytes, cholangiocytes and hepatic stellate cells), others are specialised versions of cell types also found in other organs, such as liver sinusoidal endothelial cells (LSECs) and Kupffer cells, the resident macrophages of the liver. Organs are also permeated by many other immune cell types that patrol and, importantly, modulate inflammatory activation as well as tolerance and quiescence within tissues. These immune cell populations play a critical part in the development of many diseases and must be considered when establishing advanced disease models...
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