Intracerebroventricular delivery of hematopoietic progenitors results in rapid and robust engraftment of microglia-like cells

Capotondo, Alessia; Milazzo, Rita; García-Manteiga, José Manuel; Cavalca, Eleonora; Montepeloso, Annita; Garrison, Brian S.; Peviani, Marco; Rossi, Derrick J.; Biffi, Alessandra

doi:10.1126/sciadv.1701211

Cited by 44 publications

(53 citation statements)

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“…The cell's precise origin, ontogeny and identifying markers in human are still remain elusive [47][48][49]. In adult brain, either in normal or disease state, it is unclear whether the microglia originate solely from cells present in the brain from fetal origins or if there is further input into CNS from HSPC derived myeloid cells [50][51][52]. While monocytes enter the CNS under steady state and diseased conditions and are transformed into microglial-like cells their "true identity" remains uncertain [41,50,53].…”

Section: Discussionmentioning

confidence: 99%

Human Interleukin-34 facilitates microglia-like cell differentiation and persistent HIV-1 infection in humanized mice

Mathews

Woods

Katano

et al. 2019

Mol Neurodegeneration

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Background: Microglia are the principal innate immune defense cells of the centeral nervous system (CNS) and the target of the human immunodeficiency virus type one (HIV-1). A complete understanding of human microglial biology and function requires the cell's presence in a brain microenvironment. Lack of relevant animal models thus far has also precluded studies of HIV-1 infection. Productive viral infection in brain occurs only in human myeloid linage microglia and perivascular macrophages and requires cells present throughout the brain. Once infected, however, microglia become immune competent serving as sources of cellular neurotoxic factors leading to disrupted brain homeostasis and neurodegeneration.Methods: Herein, we created a humanized bone-marrow chimera producing human "microglia like" cells in NOD. Cg-Prkdc scid Il2rg tm1Sug Tg(CMV-IL34)1/Jic mice. Newborn mice were engrafted intrahepatically with umbilical cord blood derived CD34+ hematopoietic stem progenitor cells (HSPC). After 3 months of stable engraftment, animals were infected with HIV-1 ADA , a myeloid-specific tropic viral isolate. Virologic, immune and brain immunohistology were performed on blood, peripheral lymphoid tissues, and brain.Results: Human interleukin-34 under the control of the cytomegalovirus promoter inserted in NSG mouse strain drove brain reconstitution of HSPC derived peripheral macrophages into microglial-like cells. These human cells expressed canonical human microglial cell markers that included CD14, CD68, CD163, CD11b, ITGB2, CX3CR1, CSFR1, TREM2 and P2RY12. Prior restriction to HIV-1 infection in the rodent brain rested on an inability to reconstitute human microglia. Thus, the natural emergence of these cells from ingressed peripheral macrophages to the brain could allow, for the first time, the study of a CNS viral reservoir. To this end we monitored HIV-1 infection in a rodent brain. Viral RNA and HIV-1p24 antigens were readily observed in infected brain tissues. Deep RNA sequencing of these infected mice and differential expression analysis revealed human-specific molecular signatures representative of antiviral and neuroinflammatory responses.Conclusions: This humanized microglia mouse reflected human HIV-1 infection in its known principal reservoir and showed the development of disease-specific innate immune inflammatory and neurotoxic responses mirroring what can occur in an infected human brain.

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Section: Discussionmentioning

confidence: 99%

Human Interleukin-34 facilitates microglia-like cell differentiation and persistent HIV-1 infection in humanized mice

Mathews

Woods

Katano

et al. 2019

Mol Neurodegeneration

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“…To begin to address this challenge, we and others performed initial experiments to determine the feasibility of transplanting human microglia or hematopoietic stem cells (HSCs) into the brains of immunodeficient mice (Abud et al, 2017;Bennett et al, 2018;Capotondo et al, 2017). Yet, to date no studies have thoroughly examined and validated the phenotype, transcriptional profile, and functional responses of engrafted human microglia to injury or disease-associated pathology, steps that are critical for determining the applicability of this approach.…”

Section: Introductionmentioning

confidence: 99%

Development of a Chimeric Model to Study and Manipulate Human Microglia In Vivo

Hasselmann

Coburn

England

et al. 2019

Neuron

271

309

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iPSC-derived microglia offer a powerful tool to study microglial homeostasis and diseaseassociated inflammatory responses. Yet, microglia are highly sensitive to their environment, exhibiting transcriptomic deficiencies when kept in isolation from the brain. Furthermore, species-specific genetic variations demonstrate that rodent microglia fail to fully recapitulate the human condition. To address this, we developed an approach to study human microglia within a surrogate brain environment. Transplantation of iPSC-derived hematopoieticprogenitors into the postnatal brain of humanized, immune-deficient mice results in contextdependent differentiation into microglia and other CNS macrophages, acquisition of an ex vivo human microglial gene signature, and responsiveness to both acute and chronic insults. Most notably, transplanted microglia exhibit robust transcriptional responses to A-plaques that only partially overlap with that of murine microglia, revealing new, human-specific Aresponsive genes. We therefore propose that this chimeric model can provide a powerful new system to examine the in vivo function of patient-derived and genetically-modified microglia.

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“…Within the brain, phagocytosis is mainly executed by microglia and blood infiltrating monocytes that differentiate into microglia‐like cells within the brain milieu (Capotondo et al, ). Phagocytic microglia undergo morphological changes, acquiring a macrophage‐like morphology with retraction of processes and enlargement of the cell body.…”

Section: Introductionmentioning

confidence: 99%

Microglial phagocytosis in aging and Alzheimer's disease

Gabandé‐Rodríguez

Keane

Capasso

2019

J of Neuroscience Research

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Intracerebroventricular delivery of hematopoietic progenitors results in rapid and robust engraftment of microglia-like cells

Abstract: We report a novel method to generate morphologically, antigenically and transcriptionally dependable microglia-like cells in vivo.

Cited by 44 publications

References 50 publications

Human Interleukin-34 facilitates microglia-like cell differentiation and persistent HIV-1 infection in humanized mice

Human Interleukin-34 facilitates microglia-like cell differentiation and persistent HIV-1 infection in humanized mice

Development of a Chimeric Model to Study and Manipulate Human Microglia In Vivo

Microglial phagocytosis in aging and Alzheimer's disease

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