Differentiation of Induced Pluripotent Stem Cells Into Chondrocytes: Methods and Applications for Disease Modeling and Drug Discovery

Abstract

Induced pluripotent stem cell (iPSC) technology allows pathomechanistic and therapeutic investigation of human heritable disorders affecting tissue types whose collection from patients is difficult or even impossible. Among them are cartilage diseases. Over the past decade, iPSC‐chondrocyte disease models have been shown to exhibit several key aspects of known disease mechanisms. Concurrently, an increasing number of protocols to differentiate iPSCs into chondrocytes have been published, each with its respective (dis)advantages. In this review we provide a comprehensive overview of the different differentiation approaches, the hitherto described iPSC‐chondrocyte disease models and mechanistic and/or therapeutic insights that have been derived from their investigation, and the current model limitations. Key lessons are that the most appropriate differentiation approach is dependent upon the cartilage disease under investigation and that further optimization is still required to recapitulate the in vivo cartilage. © 2022 American Society for Bone and Mineral Research (ASBMR).

Modeling human skeletal development using human pluripotent stem cells

“…Our iPSC-chondrocyte differentiation method has several advantages over current methods (see ref. 13 for a detailed review). It is relatively simple, uses defined media, and produces uniform cartilage organoids without requiring an intermediate flow sorting step.…”

“…A number of methodologies have been used to differentiate pluripotent stem cells in vitro to chondrocytes (reviewed in ref. 13 ). These initially differentiated hPSCs to PDGFRa+ primitive streak mesoderm, which was then directed to form SOX9+ cartilage precursors, passing via either lateral plate or paraxial mesoderm intermediates.…”

High Bone Mass Disorders: New Insights From Connecting the Clinic and the Bench

“…2). (120,121) Fish models Zebrafish (Danio rerio), or occasionally medaka fish (Oryzias latipes), are also used to model human diseases. They are relatively cheap to house, amenable to genetic and pharmacological manipulation, and accessible for skeletal imaging (Fig.…”

“…Alternatively, the use of patient-derived iPSCs in a clinical setting could be less invasive by differentiating iPSCs into specialized bone cell types using bone matrix scaffolds for laboratory testing (eg, omics, activity, morphology). (120,121) Detailed phenotyping, state-of-the art genetic screening strategies, and linking genotype-phenotype information to an affected mechanism can make a stark difference in future VUS interpretation for HBM phenotypes. Our classification of HBM genes can be a key tool here (Table 1).…”

“…Alternatively, the use of patient‐derived iPSCs in a clinical setting could be less invasive by differentiating iPSCs into specialized bone cell types using bone matrix scaffolds for laboratory testing (eg, omics, activity, morphology). ( 120 , 121 )…”