Abstract
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.
Highlights
Familial amyloid polyneuropathy (FAP) is a neurodegenerative disease caused by deposition of mutated transthyretin (TTR)-derived amyloid fibrils in several organs [1]
We found that tissue-resident macrophages are CD163 or CD206 positive, with a lower number in FAP patients compared with control patients
These results suggest that tissue-resident CD163+ or CD206+ macrophages are involved in FAP pathogenesis, and induced pluripotent stem (iPS)-myeloid lineage cells (MLs) therapy may be a novel and rational approach for the treatment of FAP
Summary
Familial amyloid polyneuropathy (FAP) is a neurodegenerative disease caused by deposition of mutated transthyretin (TTR)-derived amyloid fibrils in several organs [1]. FAP ATTR V30M patients present with polyneuropathy, thermal hyperalgesia, dysesthesia, gastrointestinal symptoms, orthostatic hypotension, and numbness in the hands and feet [6]. With disease progression, they exhibit visual impairment, heart and chronic renal failure, and death usually results within 10 years [6]. It has been suggested that heterotetrameric TTR is unstable and dissociates into monomeric TTR [15], which likely induces conformational changes [15] Based on this theory, tafamidis and diflunisal have recently been used as stabilizers of circulating tetrameric TTR [6]. These drugs are useful for the prevention of deposited TTR in tissue, the elimination effect of already deposited TTR-derived amyloid fibrils is unknown
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