Patient-Derived iPSCs and iNs—Shedding New Light on the Cellular Etiology of Neurodegenerative Diseases

Abstract

Induced pluripotent stem cells (iPSCs) and induced neuronal (iN) cells are very much touted in terms of their potential promises in therapeutics. However, from a more fundamental perspective, iPSCs and iNs are invaluable tools for the postnatal generation of specific diseased cell types from patients, which may offer insights into disease etiology that are otherwise unobtainable with available animal or human proxies. There are two good recent examples of such important insights with diseased neurons derived via either the iPSC or iN approaches. In one, induced motor neurons (iMNs) derived from iPSCs of Amyotrophic lateral sclerosis/Frontotemporal dementia (ALS/FTD) patients with a C9orf72 repeat expansion revealed a haploinsufficiency of protein function resulting from the intronic expansion and deficiencies in motor neuron vesicular trafficking and lysosomal biogenesis that were not previously obvious in knockout mouse models. In another, striatal medium spinal neurons (MSNs) derived directly from fibroblasts of Huntington’s disease (HD) patients recapitulated age-associated disease signatures of mutant Huntingtin (mHTT) aggregation and neurodegeneration that were not prominent in neurons differentiated indirectly via iPSCs from HD patients. These results attest to the tremendous potential for pathologically accurate and mechanistically revealing disease modelling with advances in the derivation of iPSCs and iNs.

MOPD I patient-derived cerebral organoids model microcephaly showing premature neurogenesis due to disrupted mitotic spindle orientation

“…Analyses of forebrain organoids from MOPD I patients showed reduced proliferation, premature neuronal differentiation, increased horizontal cell divisions in VZ-like areas, and reduced radial glial migration. Patient-derived iPSCs offer an opportunity to uncover molecular mechanisms behind microcephaly, as they have been successfully used to model human neurological disorders in vitro since they possess the same genetic make-up of the individual that they were derived from (61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73). In addition, modeling these neurodevelopmental disorders in mice is not ideal since the mouse brain is lissencephalic in nature.…”

Thrombin and the Coag-Inflammatory Nexus in Neurotrauma, ALS, and Other Neurodegenerative Disorders

“…That may be too simple, although it is a strategy worth evaluating. However, this should not be done with pre-clinical animal models due to known differences in inflammatory responses compared to humans, but in human iPSC ex vivo models that incorporate elements of the blood-spinal cord barrier (BSCB)BBB/NVU along with neurons (156, 157).…”

Clarifying the Pathophysiological Mechanisms of Neuronal Abnormalities of NF1 by Induced-Neuronal (iN) Cells from Human Fibroblasts

“…The cells directly converted to neuronal cells are called "induced-neuronal (iN) cells" and were first developed from mouse fibroblasts transfected with the three transcriptional factors Brn2, Ascl1, and Myt1l (BAM factors) [23]. Human iN cells have been utilized in neuropsychiatric research, [24,25] and several advantages have been reported that iN cells retain some of the aging-related physiological conditions that are lost in iPS cells [26,27]. Using human-derived BAM factors, we succeeded in inducing iN cells from adult human fibroblasts in 2 weeks [28][29][30][31][32].…”