Therapeutic potential of human microglia transplantation in a chimeric model of CSF1R-related leukoencephalopathy

被引:14
作者
Chadarevian, Jean Paul [1 ,2 ,3 ]
Hasselmann, Jonathan [2 ,3 ]
Lahian, Alina [1 ,2 ,3 ]
Capocchi, Joia K. [2 ]
Escobar, Adrian [3 ]
Lim, Tau En [2 ,3 ]
Le, Lauren [2 ]
Tu, Christina [2 ,3 ]
Nguyen, Jasmine [2 ]
Shabestari, Sepideh Kiani [1 ,3 ]
Carlen-Jones, William [2 ]
Gandhi, Sunil [1 ]
Bu, Guojun [4 ]
Hume, David A. [5 ]
Pridans, Clare [6 ]
Wszolek, Zbigniew K. [7 ]
Spitale, Robert C. [8 ]
Davtyan, Hayk [2 ,3 ]
Blurton-Jones, Mathew [1 ,2 ,3 ]
机构
[1] Univ Calif Irvine, Dept Neurobiol & Behav, Irvine, CA 92697 USA
[2] Univ Calif Irvine, Inst Memory Impairments & Neurol Disorders, Irvine, CA 92697 USA
[3] Univ Calif Irvine, Sue & Bill Gross Stem Cell Res Ctr, Irvine, CA 92697 USA
[4] Hong Kong Univ Sci & Technol, Div Life Sci, Hong Kong, Peoples R China
[5] Univ Queensland, Mater Res Inst, Brisbane, Qld, Australia
[6] Univ Edinburgh, Ctr Inflammat Res, Edinburgh, Scotland
[7] Mayo Clin, Dept Neurol, Jacksonville, FL USA
[8] Univ Calif Irvine, Dept Pharmaceut Sci, Irvine, CA USA
关键词
HEREDITARY DIFFUSE LEUKOENCEPHALOPATHY; ADULT-ONSET LEUKOENCEPHALOPATHY; AXONAL SPHEROIDS; CELL THERAPY; MOUSE MODEL; BRAIN; GLIA; LEUKODYSTROPHY;
D O I
10.1016/j.neuron.2024.05.023
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Microglia replacement strategies are increasingly being considered for the treatment of primary microgliopathies like adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). However, available mouse models fail to recapitulate the diverse neuropathologies and reduced microglia numbers observed in patients. In this study, we generated a xenotolerant mouse model lacking the fms- intronic regulatory element (FIRE) enhancer within Csf1r, which develops nearly all the hallmark pathologies associated with ALSP. Remarkably, transplantation of human induced pluripotent stem cell (iPSC)-derived microglial (iMG) progenitors restores a homeostatic microglial signature and prevents the development of axonal spheroids, white matter abnormalities, reactive astrocytosis, and brain calcifications. Furthermore, transplantation of CRISPR-corrected ALSP-patient-derived iMG reverses pre-existing spheroids, astrogliosis, and calcification pathologies. Together with the accompanying study by Munro and colleagues, our results demonstrate the utility of FIRE mice to model ALSP and provide compelling evidence that iMG transplantation could offer a promising new therapeutic strategy for ALSP and perhaps other microglia-associated neurological disorders.
引用
收藏
页码:2686 / 2707.e8
页数:31
相关论文
共 101 条
[1]   Blood GFAP as an emerging biomarker in brain and spinal cord disorders [J].
Abdelhak, Ahmed ;
Foschi, Matteo ;
Abu-Rumeileh, Samir ;
Yue, John K. ;
D'Anna, Lucio ;
Huss, Andre ;
Oeckl, Patrick ;
Ludolph, Albert C. ;
Kuhle, Jens ;
Petzold, Axel ;
Manley, Geoffrey T. ;
Green, Ari J. ;
Otto, Markus ;
Tumani, Hayrettin .
NATURE REVIEWS NEUROLOGY, 2022, 18 (03) :158-172
[2]   iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases [J].
Abud, Edsel M. ;
Ramirez, Ricardo N. ;
Martinez, Eric S. ;
Healy, Luke M. ;
Nguyen, Cecilia H. H. ;
Newman, Sean A. ;
Yeromin, Andriy V. ;
Scarfone, Vanessa M. ;
Marsh, Samuel E. ;
Fimbres, Cristhian ;
Caraway, Chad A. ;
Fote, Gianna M. ;
Madany, Abdullah M. ;
Agrawal, Anshu ;
Kayed, Rakez ;
Gylys, Karen H. ;
Cahalan, Michael D. ;
Cummings, Brian J. ;
Antel, Jack P. ;
Mortazavi, Ali ;
Carson, Monica J. ;
Poon, Wayne W. ;
Blurton-Jones, Mathew .
NEURON, 2017, 94 (02) :278-+
[3]  
Alturkustani Murad, 2020, Free Neuropathol, V1, DOI 10.17879/freeneuropathology-2020-2971
[4]   Microglial dyshomeostasis drives perineuronal net and synaptic loss in a CSF1R+/- mouse model of ALSP, which can be rescued via CSF1R inhibitors [J].
Arreola, Miguel A. ;
Soni, Neelakshi ;
Crapser, Joshua D. ;
Hohsfield, Lindsay A. ;
Elmore, Monica R. P. ;
Matheos, Dina P. ;
Wood, Marcelo A. ;
Swarup, Vivek ;
Mortazavi, Ali ;
Green, Kim N. .
SCIENCE ADVANCES, 2021, 7 (35)
[5]   The developmental origin of brain tumours: a cellular and molecular framework [J].
Azzarelli, Roberta ;
Simons, Benjamin D. ;
Philpott, Anna .
DEVELOPMENT, 2018, 145 (10)
[6]   Focal Increases of Axoplasmic Ca2+, Aggregation of Sodium-Calcium Exchanger, N-type Ca2+ Channel, and Actin Define the Sites of Spheroids in Axons Undergoing Oxidative Stress [J].
Barsukova, Anna G. ;
Forte, Michael ;
Bourdette, Dennis .
JOURNAL OF NEUROSCIENCE, 2012, 32 (35) :12028-12037
[7]   Serum Glial Fibrillary Acidic Protein (GFAP) Is a Marker of Disease Severity in Frontotemporal Lobar Degeneration [J].
Benussi, Alberto ;
Ashton, Nicholas J. ;
Karikari, Thomas K. ;
Gazzina, Stefano ;
Premi, Enrico ;
Benussi, Luisa ;
Ghidoni, Roberta ;
Rodriguez, Juan Lantero ;
Emersic, Andreja ;
Binetti, Giuliano ;
Fostinelli, Silvia ;
Giunta, Marcello ;
Gasparotti, Roberto ;
Zetterberg, Henrik ;
Blennow, Kaj ;
Borroni, Barbara .
JOURNAL OF ALZHEIMERS DISEASE, 2020, 77 (03) :1129-1141
[8]   Dominant-acting CSF1R variants cause microglial depletion and altered astrocytic phenotype in zebrafish and adult-onset leukodystrophy [J].
Berdowski, Woutje M. ;
van der Linde, Herma C. ;
Breur, Marjolein ;
Oosterhof, Nynke ;
Beerepoot, Shanice ;
Sanderson, Leslie ;
Wijnands, Lieve I. ;
de Jong, Patrick ;
Tsai-Meu-Chong, Elisa ;
de Valk, Walter ;
de Witte, Moniek ;
van IJcken, Wilfred F. J. ;
Demmers, Jeroen ;
van der Knaap, Marjo S. ;
Bugiani, Marianna ;
Wolf, Nicole I. ;
van Ham, Tjakko J. .
ACTA NEUROPATHOLOGICA, 2022, 144 (02) :211-239
[9]   Capillary-associated microglia regulate vascular structure and function through PANX1-P2RY12 coupling in mice [J].
Bisht, Kanchan ;
Okojie, Kenneth A. ;
Sharma, Kaushik ;
Lentferink, Dennis H. ;
Sun, Yu-Yo ;
Chen, Hong-Ru ;
Uweru, Joseph O. ;
Amancherla, Saipranusha ;
Calcuttawala, Zainab ;
Campos-Salazar, Antony Brayan ;
Corliss, Bruce ;
Jabbour, Lara ;
Benderoth, Jordan ;
Friestad, Bria ;
Mills, William A. ;
Isakson, Brant E. ;
Tremblay, Marie-Eve ;
Kuan, Chia-Yi ;
Eyo, Ukpong B. .
NATURE COMMUNICATIONS, 2021, 12 (01)
[10]   Microglial reduction of colony stimulating factor-1 receptor expression is sufficient to confer adult onset leukodystrophy [J].
Biundo, Fabrizio ;
Chitu, Violeta ;
Shlager, Gabriel G. L. ;
Park, Eun S. ;
Gulinello, Maria E. ;
Saha, Kusumika ;
Ketchum, Harmony C. ;
Fernandes, Christopher ;
Gokhan, Solen ;
Mehler, Mark F. ;
Stanley, E. Richard .
GLIA, 2021, 69 (03) :779-791