Current Challenges of iPSC-Based Disease Modeling and Therapeutic Implications

Abstract

Induced pluripotent stem cell (iPSC)-based disease modelling and the cell replacement therapy approach have proven to be very powerful and instrumental in biomedical research and personalized regenerative medicine as evidenced in the past decade by unraveling novel pathological mechanisms of a multitude of monogenic diseases at the cellular level and the ongoing and emerging clinical trials with iPSC-derived cell products. iPSC-based disease modelling has sparked widespread enthusiasm and has presented an unprecedented opportunity in high throughput drug discovery platforms and safety pharmacology in association with three-dimensional multicellular organoids such as personalized organs-on-chips, gene/base editing, artificial intelligence and high throughput “omics” methodologies. This critical review summarizes the progress made in the past decade with the advent of iPSC discovery in biomedical applications and regenerative medicine with case examples and the current major challenges that need to be addressed to unleash the full potential of iPSCs in clinical settings and pharmacology for more effective and safer regenerative therapy.

Adenoviral Vectors Meet Gene Editing: A Rising Partnership for the Genomic Engineering of Human Stem Cells and Their Progeny

“…Crucially, cellular reprogramming overcomes the ethical concerns associated with hESCs and offers the possibility for generating and differentiating hiPSCs from virtually any individual into tissue-specific cell types. These capabilities permit in vitro disease modeling and drug screenings [124,125]. Moreover, hiPSCs open the perspective for autologous cell transplantation therapies for repairing tissues and organs affected by injuries or, when combined with gene-editing technologies, inherited disorders [124,125] (Figure 4).…”

The Challenge of Bringing iPSCs to the Patient

“…This is mainly due to their self-renewal capacity and the possibility to potentially give rise to any kind of cell [34]. Nevertheless, iPSCs differentiation protocols towards different cell types require vast enhancement of efficiency rates to obtain the proper maturation, as we will discuss later [35]. Once this is accomplished, the application of iPSCs technology could ideally satisfy the demand that cannot be fulfilled only by organ transplantation [36].…”

“…As reviewed earlier, the cost and time required for autologous therapies to become a reality for the patients are, unfortunately, two of the main reasons why they seem to be far from the clinics [35]. Perhaps the alternative of allogeneic transplants could be the optimal solution, but the problems associated with immunogenicity are the main drawback.…”

Cardiotoxicity and Heart Failure: Lessons from Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Anticancer Drugs

“…Thus, several efforts were made to the development of human-relevant models (for a review, see Reference [1]). More recently, human-induced pluripotent stem cells (hiPSCs) were intensively applied as disease modeling to elucidate pathological mechanisms of multifactorial and monogenic diseases at the cellular level [2]. Sophisticated differentiation protocols were established allowing generation of any somatic cell type (e.g., cardiomyocytes, neurons, and hepatocytes) from hiPSCs, derived from individual patients or healthy individuals, with the hope of developing patient-specific therapies (also known as personalized medicine) (for a review, see References [1,2]).…”

“…More recently, human-induced pluripotent stem cells (hiPSCs) were intensively applied as disease modeling to elucidate pathological mechanisms of multifactorial and monogenic diseases at the cellular level [2]. Sophisticated differentiation protocols were established allowing generation of any somatic cell type (e.g., cardiomyocytes, neurons, and hepatocytes) from hiPSCs, derived from individual patients or healthy individuals, with the hope of developing patient-specific therapies (also known as personalized medicine) (for a review, see References [1,2]). However, there are several challenges of hiPSC-based disease modeling, cell therapy, and drug discovery (e.g., the immaturity and tumorigenicity of the somatic cells) that need to be overcome for optimization of the stem-cell-based applications (for a review, see References [1,2]).…”