Advancing Renewable Normal Human Cell Assays for Drug Discovery

Preclinical ResearchA major shortcoming in current drug development evaluation assays is the routine absence of renewable normal human tissue cells. Renewable tumor‐derived and transformed cell lines are pervasive in human cell culture panels used in drug screens and for drug evaluations. Although there are examples of inclusion of preparations of primary human tissue cells (e.g., human hepatocytes), the quality of these materials is variable and their availability is unreliable. The absence of renewable normal tissue cells in drug assays reflects a normal characteristic of most mature cells in human tissues. With few exceptions, they are terminally differentiated and do not divide, in vivo or in vitro, and those which do divide are developmentally programmed to undergo a permanent cell cycle arrest after a limited number of divisions. Because of these intrinsic tissue cell properties, producing normal human tissue cells in sufficient quantity for routine use in drug evaluation studies has proven essentially impossible. Tissue‐specific distributed stem cells ( DSCs ), which divide by asymmetric self‐renewal to continuously renew mature differentiated tissue cells, may be the key to addressing this unmet need for more effective drug discovery. However, DSCs , which are exceedingly scarce in tissues, are notoriously difficult to identify and, previously, inexplicably refractory to expansion in culture. Here, recent advances in the discovery of DSC ‐specific biomarkers and methods for ex vivo expansion of human DSC strains are discussed in terms of their potential to enable a new era of drug discovery and development by advancing renewable normal human cell assays into routine practice.