The 3R principle: advancing clinical application of human pluripotent stem cells

Abstract

The first derivation of human embryonic stem cells brought with it a clear understanding that animal models of human disease might be replaced by an unlimited supply of human cells for research, drug discovery, and drug development. With the advent of clinical trials using human pluripotent stem cell-based therapies, it is both timely and relevant to reflect on factors that will facilitate future translation of this technology. Human pluripotent cells are increasingly being used to investigate the molecular mechanisms that underpin normal and pathological human development. Their differentiated progeny are also being used to identify novel pharmaceuticals, to screen for toxic effects of known chemicals, and to investigate cell or tissue transplantation strategies. The intrinsic assumption of these research efforts is that the information gained from these studies will be more accurate, and therefore of greater relevance, than traditional investigations based on animal models of human disease and injury. This review will therefore evaluate how animals and animal-derived products are used for human pluripotent stem cell research, and will indicate how efforts to further reduce or remove animals and animal products from this research will increase the clinical translation of human pluripotent stem cell technologies through drug discovery, toxicology screening, and cell replacement therapies.

Defined Culture of Human Embryonic Stem Cells and Xeno-Free Derivation of Retinal Pigmented Epithelial Cells on a Novel, Synthetic Substrate

“…The advent of using pluripotent stem cell‐derived therapies to treat human diseases necessitates good manufacturing practices and, preferably, defined culture conditions that do not use xenogeneic products [25]. However, some of the current methods used to produce hESC‐RPE use Matrigel, a mixture of ECM proteins harvested from the Engelbreth‐Holm‐Swarm mouse sarcoma [17, 18, 54].…”

Alzheimer disease research in the 21st century: past and current failures, new perspectives and funding priorities

“…One approach that has been suggested is to validate data obtained in non-mammalian models in a small number of animals before moving to human tissues/cultures or clinical trials, thereby contributing to a reduction of the use of animals, according to the 3Rs principle envisioned in toxicology and biomedical research [85]. However, it should also be considered that intermediate validation steps in non-human mammals might generate false negative results, possibly invalidating results that might actually be proven valuable in human settings.…”

Stems cells, big data and compendium-based analyses for identifying cell types, signalling pathways and gene regulatory networks

“…While valuable knowledge has been gained through decades of animal studies, the ability for animal models to specifically predict treatment responses in human patients is questionable (Shanks et al 2009). This has led both academic researchers and the pharmaceutical industry to investigate human stem cells as an alternative source of information for both basic research and drug discovery (Cressey 2012;O'Connor 2013).…”

“…Human pluripotent stem (PS) cells offer a unique opportunity to rapidly progress our understanding of how environmental cues modulate signalling cascades and TG sets. This is due to key properties of human PS cells (O'Connor 2013;O'Connor et al 2011a;Ungrin et al 2007), including the ability to: 1) Self-renew (i.e., proliferate while retaining developmental potential), thereby enabling production of extremely large numbers of human cells in vitro 2) Differentiate into essentially any desired human cell type for research and clinical applications 3) Enable simple and highly targeted gene modification through technologies such as Crispr/Cas9 4) Obtain both normal and disease-specific human PS cells, either from donated IVF embryos (i.e., embryonic stem cells, or ES cells), by cell reprogramming (i.e., induced pluripotent stem cells) or by genome modification of these PS cell types 5) Directly model human biology without confounding species-specific differences that can arise through studies of animal models…”