Table 1 The use of iMphs for hereditary disease modeling and drug testing

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

(gp91^phox, AR p47^phox or p22^phox deficiencies)

–

CGD-iMphs: an impaired production of ROS; the cells can be cryopreserved

Klatt et al. [62]

Healthy donor;

CGD patient

(p47^phox-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

(gp91^phox 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*

R47H^het iPSCs*

R47H^hom 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*

R47H^het iPSCs*

R47H^hom 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