Human cell models for inherited platelet disorders: strengths, limitations and emerging technologies

Abstract

Inherited platelet disorders (IPD) comprise a clinically and genetically heterogeneous group of conditions affecting platelet number, function, or both. Although next-generation sequencing has accelerated gene discovery, it has also produced a growing number of variants of uncertain significance, creating a pressing need for experimental systems that can establish causal genotype–phenotype relationships. Because megakaryocytes are scarce in the bone marrow and murine models incompletely recapitulate human platelet biology, human cell-based models are indispensable for studying megakaryopoiesis and platelet formation. Here we review the evolution of such models and their application to IPD research. Leukemia-derived megakaryocytic cell lines provided the first genetically tractable models but incompletely reproduce physiological thrombopoiesis. Megakaryocytes derived from primary hematopoietic stem cells remain the gold standard for patient-specific disease modeling, offering high biological relevance but requiring donor material and being subject to significant inter-donor variability. Induced pluripotent stem cells provide a renewable source of megakaryocytes for disease modeling, although efficient platelet production and functional characterization remain challenging. In contrast, the immortalized megakaryocyte cell line offers a scalable and genetically tractable platform that faithfully recapitulates megakaryocyte maturation, supports platelet production, and enables selected platelet function assays. We further discuss emerging three-dimensional and organoid systems that begin to capture the complexity of the bone-marrow niche. Across these platforms we discuss applications in disease mechanism discovery, functional validation of novel variants, and preclinical evaluation of therapies. No single model is universally optimal; rather, model choice should be guided by the biological question, with validation against primary patient material remaining essential.