Modelling human disease with pluripotent stem cells

Abstract

Recent progress in the field of cellular reprogramming has opened up the doors to a new era of disease modelling, as pluripotent stem cells representing a myriad of genetic diseases can now be produced from patient tissue. These cells can be expanded and differentiated to produce a potentially limitless supply of the affected cell type, which can then be used as a tool to improve understanding of disease mechanisms and test therapeutic interventions. This process requires high levels of scrutiny and validation at every stage, but international standards for the characterisation of pluripotent cells and their progeny have yet to be established. Here we discuss the current state of the art with regard to modelling diseases affecting the ectodermal, mesodermal and endodermal lineages, focussing on studies which have demonstrated a disease phenotype in the tissue of interest. We also discuss the utility of pluripotent cell technology for the modelling of cancer and infectious disease. Finally, we spell out the technical and scientific challenges which must be addressed if the field is to deliver on its potential and produce improved patient outcomes in the clinic.

Figure 1. The process of creating improved patient care using reprogramming and differentiation of donor tissue

A biopsy is taken from a patient, reprogrammed to a state of pluripotency before being differentiated to a cell type of interest. Disease-specific tissues can then be used to improve current understanding of disease states and aid the drug development process. The induction of pluripotency allows for limitless expandability of the cell population. Validation is critical to the success of the process; here we identify six key steps which must be addressed. (A). Tissue from the patient must present the genetic traits of the disease state. (B). Reprogrammed cells must demonstrate pluripotency as assessed through a rigorous, standardised validation process. (C). Differentiated cells must demonstrate the key characteristics of the mature cell type as assessed by marker expression and functionality. (D). The differentiated cells should present the disease phenotype. (E). Genetic and drug interventions should be able to correct the phenotype. The cell model should predict the response of current therapies. This will lead to increased knowledge of the disease mechanism. (F). Patient benefit must be assessed through clinical trials.