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CNS-wide repopulation by hematopoietic-derived microglia-like cells corrects progranulin deficiency in mice

Author

Listed:
  • Pasqualina Colella

    (Stanford University School of Medicine)

  • Ruhi Sayana

    (Stanford University School of Medicine)

  • Maria Valentina Suarez-Nieto

    (Stanford University School of Medicine)

  • Jolanda Sarno

    (Stanford University
    Fondazione IRCCS San Gerardo dei Tintori)

  • Kwamina Nyame

    (Stanford University
    Stanford University
    Stanford University)

  • Jian Xiong

    (Stanford University
    Stanford University
    Stanford University)

  • Luisa Natalia Pimentel Vera

    (Stanford University School of Medicine)

  • Jessica Arozqueta Basurto

    (Stanford University School of Medicine)

  • Marco Corbo

    (Inc)

  • Anay Limaye

    (Stanford University School of Medicine
    Inc)

  • Kara L. Davis

    (Stanford University)

  • Monther Abu-Remaileh

    (Stanford University
    Stanford University
    Stanford University)

  • Natalia Gomez-Ospina

    (Stanford University School of Medicine)

Abstract

Hematopoietic stem cell transplantation can deliver therapeutic proteins to the central nervous system (CNS) through transplant-derived microglia-like cells. However, current conditioning approaches result in low and slow engraftment of transplanted cells in the CNS. Here we optimized a brain conditioning regimen that leads to rapid, robust, and persistent microglia replacement without adverse effects on neurobehavior or hematopoiesis. This regimen combines busulfan myeloablation and six days of Colony-stimulating factor 1 receptor inhibitor PLX3397. Single-cell analyses revealed unappreciated heterogeneity of microglia-like cells with most cells expressing genes characteristic of homeostatic microglia, brain-border-associated macrophages, and unique markers. Cytokine analysis in the CNS showed transient inductions of myeloproliferative and chemoattractant cytokines that help repopulate the microglia niche. Bone marrow transplant of progranulin-deficient mice conditioned with busulfan and PLX3397 restored progranulin in the brain and eyes and normalized brain lipofuscin storage, proteostasis, and lipid metabolism. This study advances our understanding of CNS repopulation by hematopoietic-derived cells and demonstrates its therapeutic potential for treating progranulin-dependent neurodegeneration.

Suggested Citation

  • Pasqualina Colella & Ruhi Sayana & Maria Valentina Suarez-Nieto & Jolanda Sarno & Kwamina Nyame & Jian Xiong & Luisa Natalia Pimentel Vera & Jessica Arozqueta Basurto & Marco Corbo & Anay Limaye & Kar, 2024. "CNS-wide repopulation by hematopoietic-derived microglia-like cells corrects progranulin deficiency in mice," Nature Communications, Nature, vol. 15(1), pages 1-26, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49908-4
    DOI: 10.1038/s41467-024-49908-4
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