Table 1 Detailed description of reprogramming, differentiation strategies, resulting aging/disease phenotype, and relevant reports summarized
From: Strategies for modeling aging and age-related diseases
Aging/Age-related diseases | Key phenotypic markers | Mutation type | Differentiation process | Strategy | Aging/disease phenotype | Reports |
|---|---|---|---|---|---|---|
Aging induced model | DNA damage Increase in Mito-ROS Increase in senescence/ p21/ β-gal activity lipofuscin accumulation Telomere shortening | Null | Old/young donor IPSC --> fibroblasts | Progerin overexpression in IPSC-derived fibroblasts | Fibroblasts displayed: DNA damage Increase in Mito-ROS Decrease in telomere length Increase in % short telomeres Increase in senescence | Miller et al., 2013 |
Null | Old/young donor IPSC --> mDA neurons | Progerin overexpression in IPSC-derived mDA neurons | mDA neurons displayed: DNA damage Increase in Mito-ROS Dendrite degeneration Inclusion bodies Reduced TH+ neurons | Miller et al., 2013 | ||
Null | IPSC --> cardiomyocyte | Long-term culture of IPSC-derived cells | Induced cardiomyocytes displayed: Accelerated senescence Increase in p21 and p53 lipofuscin accumulation | Acun et al., 2019 | ||
Null | IPSC --> cardiomyocyte | 3D tissue model with cells aged by long-term culture | 3D tissue model displayed: lower survival rate less proliferative capacity higher β-gal activity high ROS lower cardiac beating velocity | Acun et al., 2019 | ||
Null | IPSC --> mDA neurons | Telomere manipulation | mDA neurons displayed: DNA damage Increased Mito-ROS loss of mDA neuron marker TH | Vera et al., 2016 | ||
Null | IPSC --> Brain organoid | Organoid exposed to ionizing radiation 0.5 or 2 Gy of 250 MeV protons for 30 mins, 24 h, 48 h | Cerebral organoid displayed: Increase in DNA damage | Oyefeso et al., 2023 | ||
Null | IPSC --> Brain organoid | Organoid exposed to hypoxic conditions 0.1 O2 for 24 h | Cerebral organoid displayed: BBB dysfunction increased oxidative stress elevated secretion of inflammatory cytokines such as IL-1β, TNFα, IL-6 | Nzou et al., 2020 | ||
Werner syndrome-based model | Telomere dysfunction Premature senescence | WRN | WS fibroblasts--> IPSC -- > MSC | Reprogramming by OSKM+HDACi+TGFβ RI kinase I and differentiation with MSC medium containing bFGF | WS-MSC displayed: Increase in senescence reduced telomere length higher p53 expression | Cheung et al., 2014 |
WRN | WS fibroblasts--> IPSC -- > MSC | hTERT overexpression and p53 knockdown in MSC | WS-MSC displayed: Rescues premature senescence Increased telomere length | Cheung et al., 2014 Wang et al., 2018 | ||
WRN | WS fibroblasts--> IPSC -- > MSC | Gene correction of WRN in WS IPSC clones | WS-MSC displayed: Higher proliferation Rescues premature senescence Normal karyotype | Kato et al., 2021 Tu et al., 2020 | ||
Centenarian-based model | Short telomeres Increased senescence | Null | Supercentenarian (aged 114) B-LCL -- > IPSC -- > MPC | Reprogramming by OSKM | IPSC clones displayed: long telomeres normal karyotype | Lee et al., 2020 |
Null | Centenarian (aged 106,109) fibroblasts --> IPSC --> neuronal cells | Reprogramming by OSKM | IPSC clones displayed: long telomeres higher expression of igf1, igf1r, sirt2, foxo1, and sirt1 | Yagi et al., 2012 | ||
Null | Centenarian fibroblasts (aged 92,94,96,101) --> IPSC --> embryonic lineages | Reprogramming by OSKMNL/ inhibition of p53 or p21 CIP1 | IPSC clones displayed: long telomeres decrease in senescence | Lapasset et al., 2011 | ||
Alzheimer’s based model | Accumulation of amyloid-β/tau Increase in p-tau | PSEN1 A246E | FAD IPSC --> NPCs | Reprogramming by OSKM and differentiation by RA and neurosphere formation | NPCs displayed: Increase in Aβ 42/40 ratio Increase in premature differentiation and p-tau | Yang et al., 2017 |
PSEN1 A246E | FAD IPSC --> NPCs | Reprogramming by OSKM and differentiation by dual SMAD inhibition | NPCs displayed: Increase in Aβ 42/40 ratio | Sproul et al., 2014 | ||
PSEN1 V89l | FAD IPSC --> NPCs | Reprogramming by OSKM and differentiation by dual SMAD inhibition + BDNF | NPCs displayed: Increased proliferation neurite outgrowth | Pansri et al., 2021 | ||
PSEN1 A246E/ PSEN2 N141l | FAD IPSC --> neurons | Reprogramming by OSKLN and differentiation in hIPSC medium w/o bFGF | Neurons displayed: higher secretion of amyloid-β42 | Yagi et al., 2011 | ||
PSEN1A246E/H163R/M146L | FAD IPSC --> neurons | Reprogramming by OSKM and differentiation by dual SMAD inhibition | Neurons displayed: Increase in Aβ 42/40 ratio | Liu et al., 2014 | ||
PSEN1 A246E | FAD IPSC --> neurons | Reprogramming by OSKM and differentiation by dual SMAD inhibition | Neurons displayed: Mitophagy impairment Dysfunctional mitochondria | Martin-Maestro et al., 2017 | ||
APPDp | FAD IPSC --> neurons | Reprogramming by OSKM + EGFP in one third of culture and differentiation by BDNF/GDNF/cAMP | Neurons displayed: Increase in amyloid-β40/p-tau/GSK3β | Israel et al., 2012 | ||
APPDp | FAD IPSC --> neurons | Reprogramming by OSKM and differentiation by dual SMAD inhibition | Neurons displayed: Increase in Aβ42/40 ratio Increase in p-tau | Moore et al., 2015 | ||
AppDp/PSEN1 M146l, A264E | FAD IPSC --> brain organoid | 3D brain organoid (protocol as in Kadoshima et al., 2013) | Brain organoids displayed: amyloid plaque deposition hyperphosphorylation of tau endosomal abnormalities | Raja et al., 2016 | ||
PSEN1 A246E/ PSEN2 N141l | FAD IPSC --> brain organoid | 3D brain organoid (protocol as in Lancaster et al., 2014) | Brain organoids displayed: large Aβ aggregates Increase in Aβ42/40 ratio higher p-tau Developmental defects premature neuronal differentiation | Vanova et al., 2023 | ||
PSEN1 A246E | FAD IPSC --> brain organoid | 3D brain organoid (protocol as in Lancaster et al., 2014) | Brain organoids displayed: amyloid plaque deposition neurofibrillary tangles | Gonzalez et al., 2018 | ||
Isogenic APOE3, APOE4 | APOE4 isogenic IPSC lines --> brain organoid | 3D brain organoid (protocol as in Park et al., 2021) | Park et al., 2021 | |||
SAD APOE3/3, APOE4/4 | SAD IPSC --> brain organoid | 3D brain organoid (protocol as in Lancaster et al., 2014) | Brain organoids displayed: amyloid-β accumulation hyperphosphorylation of tau (independent of APOE status) | Hernandez et al., 2021 | ||
53 participants in cohort (16 particpants with clinical and pathological diagnosis of AD) | PBMC-- > IPSC--> induced neurons (iNs) | Reprogramming by sendai virus and differentiation by neurogenin-2 direct induction protocol | Neuritic plaque burden in brain correlated with intra Aβ42/40 ratio in iNs of same individual Tau tangle measures in brain negatively correlated with p-tau in iNs but p-tau levels in brain and iNs were positively correlated. APOE4/4,3/3,2/2 displayed no differences in tau levels | Valentina et al., 2021 | ||
Parkinson’s based model | Accumulation of α-synuclein Increased ROS Mitochondrial dysfunction | SNCA triplication | PD IPSC--> mDA neurons | Reprogramming by OSKM and differentiation based on dual inhibition by noggin and SB431542+Dorsomorphin | DA neurons displayed: higher levels of α-synuclein | Devine et al., 2011 |
SNCA triplication | PD IPSC--> mDA neurons | Reprogramming by OSKM and differentiation protocol as described in Byers et al., 2011 | DA neurons displayed: higher levels of α-synuclein higher oxidative stress | Byers et al., 2011 | ||
SNCA triplication/ SNCA A53T | PD IPSC--> mDA neurons | Reprogramming by OSKM and differentiation protocol as described in Kriks et al., 2011 | DA neurons displayed: intracellular accumulation α-synuclein in TH+ cells elevated α-synuclein release | Zambon et al., 2019 | ||
LRRK2 mutant G2019S | PD IPSC-- > DA neurons | Reprogramming by OSK and differentiation protocol as described in Nyugen et al., 2011 | DA neurons displayed: higher oxidative stress mitochondrial dysfunction impairment in protein degradation | Nguyen et al., 2011 | ||
PARK2/PINK1 | PD IPSC-- > DA neurons | Reprogramming by OSKM and differentiation by dual-SMAD inhibition | DA neurons displayed: mitochondrial dysfunction Increased oxidative stress elevated α-synuclein synaptic dysfunction DA accumulation | Chung et al., 2016 | ||
PINK1/LRRK2 | PD IPSC--> neurons | Reprogramming by OSK and differentiation protocol as described in Cooper et al., 2012 | Neurons displayed: Increased ROS mitochondrial dysfunction | Cooper et al., 2016 | ||
PINK1 | PD IPSC--> mDA neurons | Reprogramming by OSKM and differentiation protocol as described in Chambers et al., 2009 | DA neurons displayed: impaired mitochondrial recruitment of PINK1 | Seibler et al.,2011 | ||
PARK2/PINK1 | PD IPSC-- > DA neurons | Reprogramming by OSKM and differentiation protocol as described in Shaltouki et al., 2015 | DA Neurons displayed: synuclein accumulation mitochondrial dysfunction | Shaltouki et al., 2015 | ||
p.D620N VPS35 | PD IPSC-- > DA neurons | Reprogramming by OSKM and differentiation protocol as described in Hanss et al., 2021 | DA Neurons displayed: synuclein accumulation mitochondrial dysfunction Impaired mitochondrial respiration Increased ROS | Hanss et al., 2021 | ||
p.D620N VPS35 | PD IPSC-- > DA neurons | Reprogramming by OSKM and differentiation protocol as described in Doi et al., 2014 | DA Neurons displayed: synuclein accumulation in TH+ cells Endosomal dysfunction | Bono et al., 2020 | ||
LRRK2 G2019S | PD IPSC-- > 3D organoids | 3D organoid protocol as described in Fiore et al., 2022 (Matrigel based) | DA neurons displayed: higher levels of α-synuclein | Fiore et al., 2022 | ||
Null | IPSC-derived brain endothelial cells, pericytes, astrocytes, microglia, and dopaminergic neurons--> Brain chip model of substantia nigra (exposed to α-Syn fibrils) | Substantia nigra brain chip model based on organ-on-chips technology to recapitulate synucleopathy of PD | DA neurons displayed: accumulation of synuclein impaired mitochondria neuroinflammation compromised BBB function | Pediaditakis et al., 2021 |
