Scholarlink

<p>Frontotemporal dementia (FTD) is a major cause of early-onset neurodegeneration characterized by progressive behavioral, emotional, and cognitive decline. Progranulin haploinsufficiency, a leading genetic cause of familial FTD, disrupts lysosomal function, lipid metabolism, autophagy, and neuroimmune signaling across multiple cell types. Increasing evidence indicates that microglia are particularly sensitive to progranulin loss, exhibiting elevated complement activation that contributes to TDP-43 proteinopathy and neuronal dysfunction. Here, we investigate the biological role of restoring progranulin exclusively within microglia by transplanting human induced pluripotent stem cell-derived microglial progenitors into progranulin (<i>Grn</i>)-deficient mice. We find that engraftment of wild-type, but not <i>Grn</i>-deficient, human microglia restore brain-wide progranulin levels, normalize microglial transcriptional states, and ameliorate pathological, functional, and behavioral phenotypes associated with progranulin loss. Because human microglia are the only source of progranulin in this system, these findings demonstrate that microglial progranulin is sufficient to restore key aspects of cellular, circuit, and behavioral homeostasis in a progranulin-deficient FTD model. More broadly, this work highlights a central, microglia-intrinsic role for progranulin in maintaining brain function and provides a framework for dissecting microglia-specific mechanisms across FTD and related neurodegenerative disorders.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Transplantation of human iPSC-derived microglia ameliorates neuropathology and circuit dysfunction in progranulin-deficient mice

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月16日

查看全文
  • Hayk Davtyan,
  • Sarah Naguib,
  • Yuliya Voskobiynyk,
  • Jean Paul Chadarevian,
  • Joia K. Capocchi,
  • Jeannie L. Giacchino,
  • Ghazaleh Eskandari-Sedighi,
  • Vivianna DeNittis,
  • Jeremy B. Ford,
  • Ani Agababian,
  • Jasmine Nguyen,
  • Alina L. Chadarevian,
  • Madison S. Sutherland,
  • Sepideh Kiani Shabestari,
  • Kayla Tran,
  • Bret Holt,
  • Alissa L. Nana,
  • Jiasheng Zhang,
  • Salvatore Spina,
  • Man Ying Wong,
  • Lea T. Grinberg,
  • William W. Seeley,
  • Eric Huang,
  • Claire D. Clelland,
  • Shiaoching Gong,
  • Li Fan,
  • Jeanne T. Paz,
  • Mathew Blurton-Jones,
  • Li Gan

摘要

Frontotemporal dementia (FTD) is a major cause of early-onset neurodegeneration characterized by progressive behavioral, emotional, and cognitive decline. Progranulin haploinsufficiency, a leading genetic cause of familial FTD, disrupts lysosomal function, lipid metabolism, autophagy, and neuroimmune signaling across multiple cell types. Increasing evidence indicates that microglia are particularly sensitive to progranulin loss, exhibiting elevated complement activation that contributes to TDP-43 proteinopathy and neuronal dysfunction. Here, we investigate the biological role of restoring progranulin exclusively within microglia by transplanting human induced pluripotent stem cell-derived microglial progenitors into progranulin (Grn)-deficient mice. We find that engraftment of wild-type, but not Grn-deficient, human microglia restore brain-wide progranulin levels, normalize microglial transcriptional states, and ameliorate pathological, functional, and behavioral phenotypes associated with progranulin loss. Because human microglia are the only source of progranulin in this system, these findings demonstrate that microglial progranulin is sufficient to restore key aspects of cellular, circuit, and behavioral homeostasis in a progranulin-deficient FTD model. More broadly, this work highlights a central, microglia-intrinsic role for progranulin in maintaining brain function and provides a framework for dissecting microglia-specific mechanisms across FTD and related neurodegenerative disorders.