Table 1.
The use of iMphs for hereditary disease modeling and drug testing
| Target disease |
Reference | iPSC/iMph source (mutation) |
iPSC/iMph genetic modification performed in the study | iMph characteristics and other results |
|---|---|---|---|---|
| GD | Panicker et al. [26] | Patients with type 1, 2 and 3 GD | – |
GD-iMphs: a low GBA1 enzymatic activity; an accumulation of sphingolipids in the lysosomes; a defective RBC clearance iMph capacity to clear RBCs was fully restored by recombinant GBA1 and partially restored by isofagomine |
| GD and PD | Aflaki et al. [56] | Type 1and type 2 GD patients with and without parkinsonism | – |
GD-iMphs: a decreased GBA1 activity; glucosylceramide and glucosylsphingosine are stored in iMphs GD-neurons: a reduced dopamine transporter reuptake; an elevated α-synuclein levels NCGC607 drug restored GBA1 activity iMphs and reduced SNCA levels in dopaminergic neurons generated from iPSCs derived from GD patients with Parkinsonism |
| PD | Haenseler et al. [54] | Patients with early-onset PD (A53T or SNCA triplication) | – | PD-iMphs: an increased intracellular SNCA; a higher release of SNCA; a reduced phagocytic activity |
|
PD, NCL, RS |
Munn et al. [57] | Healthy donor | Introduced mutations: SNCA A53T; GRN2/GRN R493X; MECP2-КO | Engineered iMphs: a typical macrophage phenotype; an impaired phagocytic function; some transcriptomic and secretory differences compared to parental iMphs. Detailed comparison of live and cryopreserved iMphs was performed |
| CGD |
Jiang et al. [60] Brault et al. [25] |
Patients with CGD (gp91phox, AR p47phox or p22phox deficiencies) |
– | CGD-iMphs: an impaired production of ROS; the cells can be cryopreserved |
| Klatt et al. [62] |
Healthy donor; CGD patient (p47phox-deficiency) |
Introduced mutations: p47-ΔGT – |
p47-ΔGT-iMphs and CGD-iMphs: an impaired bacteria killing (E. coli); the function was restored after the correction of the mutation | |
| Flynn et al. [61] |
CGD patient (gp91phox intronic mutation) |
CRISPR/Cas9 gene correction | CGD-iMphs: a hampered oxidative burst, restored following gene correction | |
| FMF | Takata et al. [41] | FMF patient (homozygous p.Met694Val mutation of MEFV) | – | FMF-iMphs: an increased secretion of IL-1β, IL-18, TNF-α, CCL4 in response to LPS |
| TD | Zhang et al. [37] | TD patients (heterozygote at S2046R/K531N; homozygous E1005X/E1005X truncation) | – | TD-iMphs: a defective cholesterol efflux; an increased response to LPS compared to control iMphs (IL1B, IL8, TNF, CCL5) |
| Gupta et al. [66] | Healthy donor | Frameshift in ABCA1 gene (CRISPR/Cas9) | Engineered iMphs: a reduced cholesterol efflux; a higher IL-1β production; a higher response to LPS (IL1B, IL8, and CCL5) compared to isogenic control iMphs | |
| BS | Takada et al. [68] |
Healthy donors BS patients |
Introduced mutation: NOD2 R334W – |
BS-iMphs and engineered iMphs: an enhanced inflammatory response to IFN-γ |
| PAP | Suzuki et al. [70] | Children with hereditary PAP | PAP-iMphs: an impaired GM-CSF receptor signaling; a reduced expression of GM-CSF receptor dependent genes; an impaired surfactant clearance | |
| IBDs | Mukhopadhyay et al. [71] | IBD patient (homozygous splice site mutation of IL10RB) | – | IBD-iMphs: cell overactivation; a hampered antibacterial control (S. typhimurium); overexpression of genes involved in PGE2 biosynthesis; an increased PGE2 production |
| Sens et al. [73] |
Healthy donor Very-early onset IBD patient |
KO:IL10RA, IL10RB, STAT1, STAT3 - |
Engineered iMphs and IBD-iMphs: IL-10 fails to suppress LPS-induced inflammatory response | |
| CINCA | Tanaka et al. [75] | Patients with mosaic CINCA | - | CINCA-iMphs: abnormal production of IL-1β; cells are susceptible to LPS-induced pyroptosis; inhibitors of NLRP3 pathways reduced IL-1β secretion |
|
AD NHD |
McQuade et al. [80] | Healthy donors | TREM2 knockout | Engineered iMGs: a decreased cell survival; a reduced phagocytosis of apolipoprotein E and β-Amyloid; a reduced chemotaxis to SDF-1α; an impaired in vivo response to β-Amyloid |
| Reich et al. [84] |
Control iPSCs* TREM2-KO iPSCs* |
- | TREM2-KO iMGs: a stronger migration towards C5e complement; a stronger increase in intracellular Ca in response to danger signals | |
| Hall-Robets et al. [85] |
Control iPSCs* R47H iPSCs* TREM-KO iPSCs* |
- |
TREM2-KO iMGs: impaired survival, motility, phagocytosis R47H iMGs: a reduced adhesion to vitronectin; disregulation of genes involved in cell proliferation, adhesion, motility, immunity |
|
| Piers et al. [82] |
Control iPSCs* R47Hhet iPSCs* R47Hhom iPSCs* |
- | R47H iMGs: a respiratory deficit; an impaired switch to glycolysis following immune challenge; a hampered phagocytosis of β-Amyloid. PPARγ agonist normalizes glycolysis switch and phagocytosis | |
| Cosker et al. [83] |
Control iPSCs* R47Hhet iPSCs* R47Hhom iPSCs* |
- | R47H iMGs: a reduced SYK signalling and a reduced NLRP3 inflammasome response upon cell stimulation with TREM2 ligand phosphatidylserine | |
| Garcia-Reitboeck et al. [81] |
NHD patients (T66M/T66M, W50C/W50c) |
- | NHD-iMGs: reduced expression/secretion of TREM2 and iMG survival; an impaired phagocytosis of apoptotic bodies |
AD Alzheimer’s disease, AR autosomal recessive, BS Early-onset sarcoidosis or Blau syndrome, CGD chronic granulomatous disease, CINCA chronic infantile neurologic cutaneous and articular syndrome, FMF Familial Mediterranean fever, GD Gaucher disease, GRN Progranulin, IBD inflammatory bowel diseases, iMGs iPSC-derived microglia, MeCP2 methyl-CpG-binding protein 2, NCL Neuronal ceroid lipofuscinosis, NHD Nasu-Hakola disease, NLRP3 NOD-, LRR- and pyrin domain-containing protein 3, PD Parkinson’s disease, PGE2 prostaglandin E2, RBCs red blood cells, RS Rett syndrome, SNCA Αlpha-synuclein, TD Tangier disease, TREM2 Triggering receptor expressed on myeloid cells 2