Representing Diversity in the Dish: Using Patient-Derived in Vitro Models to Recreate the Heterogeneity of Neurological Disease

Abstract

Neurological diseases, including dementias such as Alzheimer's disease (AD) and fronto-temporal dementia (FTD) and degenerative motor neuron diseases such as amyotrophic lateral sclerosis (ALS), are responsible for an increasing fraction of worldwide fatalities. Researching these heterogeneous diseases requires models that endogenously express the full array of genetic and epigenetic factors which may influence disease development in both familial and sporadic patients. Here, we discuss the two primary methods of developing patient-derived neurons and glia to model neurodegenerative disease: reprogramming somatic cells into induced pluripotent stem cells (iPSCs), which are differentiated into neurons or glial cells, or directly converting (DC) somatic cells into neurons (iNeurons) or glial cells. Distinct differentiation techniques for both models result in a variety of neuronal and glial cell types, which have been successful in displaying unique hallmarks of a variety of neurological diseases. Yield, length of differentiation, ease of genetic manipulation, expression of cell-specific markers, and recapitulation of disease pathogenesis are presented as determining factors in how these methods may be used separately or together to ascertain mechanisms of disease and identify therapeutics for distinct patient populations or for specific individuals in personalized medicine projects.

Keywords: ALS; Alzheimer's disease; FTD; Huntington's disease; IPSC; Parkinson's disease; iNeuron.

Figure 1

Illustration of the generation and application of patient-derived models. Patient cells are used to generate iPSC or DC-based in vitro models of familial or sporadic disease. These models are studied to elucidate disease-contributing mechanisms and screen preclinical therapeutics, which can be translated into treatments for donor patient populations.

Figure 2

Examples of patient-derived in vitro models of neurological disease. Select examples of how patient-derived iPSC and DC neurons, astrocytes, and microglia have been used to model ALS/FTD, AD, HD, and PD. Numbers correspond to the following references: 1. Donnelly et al., ; 2. Wang et al., ; 3. Burkhardt et al., ; 4. Wen et al., ; 5. Hall et al., ; 6. Serio et al., ; 7. Barmada et al., ; 8. Qian et al., ; 9. Almeida et al., ; 10. Liu et al., ; 11. Lim et al., ; 12. Son et al., ; 13. Su et al., ; 14. Meyer et al., ; 15. Yagi et al., ; 16. Kondo et al., ; 17. Muratore et al., ; 18. Balez et al., ; 19. Sproul et al., ; 20. Jones et al., ; 21. Zhao et al., ; 22. Abud et al., ; 23. Hu et al., ; 24. Hou et al., ; 25. Nekrasov et al., ; 26. Grima et al., ; 27. Mattis et al., ; 28. Juopperi et al., ; 29. Hsiao et al., ; 30. Hsiao et al., ; 31. Liu et al., ; 32. Devine et al., ; 33. Imaizumi et al., ; 34. Seibler et al., ; 35. Haenseler et al., ; 36. Puschmann et al., .

Figure 3

Key considerations for choosing iPSCs or DC to model neurological disease.