Postmortem Human Dura Mater Cells Exhibit Phenotypic, Transcriptomic and Genetic Abnormalities that Impact their Use for Disease Modeling

Abstract

Patient-derived cells hold great promise for precision medicine approaches in human health. Human dermal fibroblasts have been a major source of cells for reprogramming and differentiating into specific cell types for disease modeling. Postmortem human dura mater has been suggested as a primary source of fibroblasts for in vitro modeling of neurodegenerative diseases. Although fibroblast-like cells from human and mouse dura mater have been previously described, their utility for reprogramming and direct differentiation protocols has not been fully established. In this study, cells derived from postmortem dura mater are directly compared to those from dermal biopsies of living subjects. In two instances, we have isolated and compared dermal and dural cell lines from the same subject. Notably, striking differences were observed between cells of dermal and dural origin. Compared to dermal fibroblasts, postmortem dura mater-derived cells demonstrated different morphology, slower growth rates, and a higher rate of karyotype abnormality. Dura mater-derived cells also failed to express fibroblast protein markers. When dermal fibroblasts and dura mater-derived cells from the same subject were compared, they exhibited highly divergent gene expression profiles that suggest dura mater cells originated from a mixed mural lineage. Given their postmortem origin, somatic mutation signatures of dura mater-derived cells were assessed and suggest defective DNA damage repair. This study argues for rigorous karyotyping of postmortem derived cell lines and highlights limitations of postmortem human dura mater-derived cells for modeling normal biology or disease-associated pathobiology. Graphical abstract

Proteome Profiling of the Dura Mater in Patients with Moyamoya Angiopathy

“…Nevertheless, our understanding of DM largely stems from the use of pre-clinical models, since cells from DM can be isolated, cultured, and utilized for several applications [ 21 , 22 , 23 ]. A direct, comparative analysis between cells isolated from the dermis and DM, through phenotypic/transcriptomic/genetic profiling, have highlighted the potential limitations of postmortem DM-derived cells for in vitro personalized medicine applications and disease modeling [ 8 ].…”

“…Interestingly, meningeal immunity is also critical to immune responses against stroke and brain injury. Although previous studies have investigated the use of DM-derived cells for personalized medicine applications and disease modeling [ 8 ], an exhaustive proteome characterization of human DM is still lacking.…”

Human Brain Organoids in Migraine Research: Pathogenesis and Drug Development

“…However, access to high quantities of such materials is limited and most of the obtained tissues are aged and reflect an end stage of the disease; hence, it is impossible to evaluate the disease onset and developmental process. In addition, in vitro modeling of the obtained tissues may show abnormalities, for example, human dura mater cells obtained postmortem have been used for the establishment of a human in vitro model that has shown phenotypic, transcriptomic, and genetic abnormalities that must be taken into account for disease modeling [ 90 ].…”