Patient-Derived Organoids Recapitulate Pathological Intrinsic and Phenotypic Features of Fibrous Dysplasia

Abstract

Fibrous dysplasia (FD) is a rare bone disorder characterized by the replacement of normal bone with benign fibro-osseous tissue. Developments in our understanding of the pathophysiology and treatment options are impeded by the lack of suitable research models. In this study, we developed an in vitro organotypic model capable of recapitulating key intrinsic and phenotypic properties of FD. Initially, transcriptomic profiling of individual cells isolated from patient lesional tissues unveiled intralesional molecular and cellular heterogeneity. Leveraging these insights, we established patient-derived organoids (PDOs) using primary cells obtained from patient FD lesions. Evaluation of PDOs demonstrated preservation of fibrosis-associated constituent cell types and transcriptional signatures observed in FD lesions. Additionally, PDOs retained distinct constellations of genomic and metabolic alterations characteristic of FD. Histological evaluation further corroborated the fidelity of PDOs in recapitulating important phenotypic features of FD that underscore their pathophysiological relevance. Our findings represent meaningful progress in the field, as they open up the possibility for in vitro modeling of rare bone lesions in a three-dimensional context and may signify the first step towards creating a personalized platform for research and therapeutic studies.

Vitamin D Attenuates Fibrotic Properties of Fibrous Dysplasia-Derived Cells for the Transit towards Osteocytic Phenotype

“…This disorder manifests with bone deformities, fractures, and chronic pain [22], often necessitating therapeutic interventions to mitigate its progression and associated symptoms. The pathogenesis of FD involves the intricate dysregulation of bone ECM formation, orchestrated by atypical mesenchymal stromal fibroblastic and pre-osteoblastic cell populations within FD lesions [23]. In this study, we sought to explore the therapeutic potential of 1,25(OH) 2 D 3 in addressing the fibrotic phenotypes and aberrant bone metabolism characteristic of FD (Figure 3).…”

“…Similarly, in conditions such as X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD), patient-derived fibroblasts have demon-strated the ability to transdifferentiate into osteoblast-like cells to recapitulate the diseaserelevant skeletal phenotype [34]. Although their relevance to FD is speculative, the shared fibroblastic phenotype expressed across various cellular subsets within FD lesions suggest the potential for interconversion between fibroblasts and other differentiated progenies of MSC [23].…”