Involvement of Macrophages in the Pathogenesis of Familial Amyloid Polyneuropathy and Efficacy of Human iPS Cell-Derived Macrophages in Its Treatment

PLoS One. 2016 Oct 3;11(10):e0163944. doi: 10.1371/journal.pone.0163944. eCollection 2016.


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.

MeSH terms

  • Adult
  • Aged
  • Amyloid / metabolism
  • Amyloid Neuropathies, Familial / etiology*
  • Amyloid Neuropathies, Familial / metabolism*
  • Amyloid Neuropathies, Familial / pathology
  • Amyloid Neuropathies, Familial / therapy
  • Antigens, CD / metabolism
  • Antigens, Differentiation, Myelomonocytic / metabolism
  • Biomarkers
  • Case-Control Studies
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Survival
  • Female
  • Humans
  • Induced Pluripotent Stem Cells / cytology*
  • Induced Pluripotent Stem Cells / metabolism
  • Lectins, C-Type / metabolism
  • Leukocytes, Mononuclear / metabolism
  • Macrophages / cytology*
  • Macrophages / metabolism*
  • Macrophages / transplantation
  • Male
  • Mannose Receptor
  • Mannose-Binding Lectins / metabolism
  • Middle Aged
  • Myocardium / metabolism
  • Myocardium / pathology
  • Phenotype
  • Prealbumin / metabolism
  • Protein Aggregation, Pathological
  • Proteolysis
  • Receptors, Cell Surface / metabolism


  • Amyloid
  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • Biomarkers
  • CD163 antigen
  • Lectins, C-Type
  • Mannose Receptor
  • Mannose-Binding Lectins
  • Prealbumin
  • Receptors, Cell Surface

Grants and funding

This study was all supported by the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan (URL;, grant numbers 15K19493 (to T. Ikeda), 26860673 (to K. Takamatsu), 24249036 and 15H04841 (to Y. Ando). These funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.