Involvement of Macrophages in the Pathogenesis of Familial Amyloid Polyneuropathy and Efficacy of Human iPS Cell-Derived Macrophages in Its Treatment.
We hypothesized that tissue-resident macrophages in familial amyloid polyneuropathy (FAP) patients will exhibit qualitative or quantitative abnormalities, that may accelerate transthyretin (TTR)-derived amyloid deposition. To evaluate this, we examined the number and subset of tissue-resident macrophages in heart tissue from amyloid-deposited FAP and control patients. In both FAP and control patients, tissue-resident macrophages in heart tissue were all Iba+/CD163+/CD206+ macrophages. However, the number of macrophages was significantly decreased in FAP patients compared with control patients. Furthermore, the proportion of intracellular TTR in CD14+ monocytes was reduced in peripheral blood compared with healthy donors. Based on these results, we next examined degradation and endocytosis of TTR in human induced pluripotent stem (iPS) cell-derived myeloid lineage cells (MLs), which function like macrophages. iPS-MLs express CD163 and CD206, and belong to the inhibitory macrophage category. In addition, iPS-MLs degrade both native and aggregated TTR in a cell-dependent manner in vitro. Further, iPS-MLs endocytose aggregated, and especially polymerized, TTR. These results suggest that decreased tissue-localized macrophages disrupt clearance of TTR-derived amyloid deposits, leading to progression of a pathological condition in FAP patients. To improve this situation, clinical application of pluripotent stem cell-derived MLs may be useful as an approach for FAP therapy.
Department of Neurology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
Genki
G
Suenaga
Department of Neurology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.|Department of Clinical Research Support Center, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
Tokunori
T
Ikeda
Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Yoshihiro
Y
Komohara
Department of Neurology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
Koutaro
K
Takamatsu
Department of Biostatistics Center, Kurume University, School of Medicine, Kurume, Japan.
Tatsuyuki
T
Kakuma
Department of Neurology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
Masayoshi
M
Tasaki
Department of Neurology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
Yohei
Y
Misumi
Department of Neurology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
Mitsuharu
M
Ueda
Department of Pathology and Experimental Medicine, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
Takaaki
T
Ito
Department of Immunogenetics, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
Satoru
S
Senju
Department of Neurology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
Yukio
Y
Ando
D000328:Adult; D000368:Aged; D000682:Amyloid / Q000378:metabolism; D028227:Amyloid Neuropathies, Familial / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D015415:Biomarkers; D016022:Case-Control Studies; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism* / Q000637:transplantation; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011228:Prealbumin / Q000378:metabolism; D066263:Protein Aggregation, Pathological; D059748:Proteolysis; D011956:Receptors, Cell Surface / Q000378:metabolism; D000098902:CD163 Antigen
D000682:Amyloid; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015415:Biomarkers; D000098902:CD163 Antigen; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011228:Prealbumin; D011956:Receptors, Cell Surface
Cancer Sci. 2012 Dec;103(12):2165-72
22957741
Circulation. 2012 Sep 4;126(10):1286-300
22949539
Lab Invest. 2013 Aug;93(8):911-20
23817086
Protein Sci. 2001 Aug;10(8):1606-13
11468357
BMJ Case Rep. 2012 Aug 18;2012:null
22907857
Neurol Ther. 2015 Dec;4(2):61-79
26662359
Pancreas. 2012 Aug;41(6):971-3
22781911
J Biochem. 1986 Nov;100(5):1215-22
3818577
Blood. 1993 Mar 15;81(6):1607-13
7680921
J Med Genet. 1994 May;31(5):351-4
8064809
Ann Med. 2015 ;47(8):625-38
26611723
Curr Med Chem. 2012;19(15):2312-23
22471980
Hum Pathol. 1991 Jun;22(6):519-27
1864584
Arthritis Rheumatol. 2015 May;67(8):2097-107
25940564
Nature. 2003 Dec 18;426(6968):905-9
14685252
Am J Physiol Regul Integr Comp Physiol. 2010 May;298(5):R1173-87
20219869
J Immunol. 2006 Oct 15;177(8):5517-23
17015738
J Immunol. 2008 Sep 15;181(6):3733-9
18768823
Liver Transpl Surg. 1998 May;4(3):236-8
9563964
Amyloid. 2014 Sep;21(3):175-84
24918964
Blood. 2009 Mar 12;113(11):2578-86
19131549
Curr Opin Pediatr. 2001 Jun;13(3):234-9
11389357
Nature. 2013 Apr 25;496(7446):445-55
23619691
Gene Ther. 2011 Sep;18(9):874-83
21430784
Stem Cell Res. 2014 Nov;13(3 Pt A):442-53
25460605
J Intern Med. 2003 Sep;254(3):225-35
12930231
Front Immunol. 2014 Dec 04;5:620
25538705
Endocrinology. 1958 Aug;63(2):256-9
13562035
Amyloid. 2016;23 (1):39-45
26763274
Blood. 2010 Oct 21;116(16):e74-80
20628149
Muscle Nerve. 2013 Feb;47(2):157-62
23169427
Am J Pathol. 2015 Oct;185(10 ):2596-606
26118749
Muscle Nerve. 2007 Oct;36(4):411-23
17554795
J Innate Immun. 2012;4(5-6):424-36
22488251
Biochem Biophys Res Commun. 1996 Jul 25;224(3):855-62
8713135
Folia Histochem Cytobiol. 2011;49(3):365-74
22038213
Front Immunol. 2015 Jan 22;5:683
25657646
Liver Transpl. 2008 Apr;14(4):563-70
18383093
Proc Jpn Acad Ser B Phys Biol Sci. 2010;86(7):694-706
20689228
Biochemistry. 1994 Feb 22;33(7):1835-42
8110786
Biochemistry. 1998 Dec 22;37(51):17851-64
9922152
Clin Immunol. 2009 Mar;130(3):338-46
18952503
J Clin Invest. 1968 Sep;47(9):2025-44
5675424
Nat Rev Immunol. 2003 Jan;3(1):23-35
12511873
Transplantation. 2015 Sep;99(9):1847-54
26308415
J Neurol Neurosurg Psychiatry. 2014 Jul;85(7):740-6
24023270
PLoS One. 2013 Jun 24;8(6):e67567
23826321
J Med Genet. 1994 Apr;31(4):293-9
8071954
Ann Med. 2004;36(5):347-54
15478309
Front Immunol. 2014 Oct 17;5:514
25368618
Neurosci Lett. 1986 May 23;66(3):311-5
3755228
Exp Eye Res. 2005 Sep;81(3):306-12
16129098