Migration-based selections of antibodies that convert bone marrow into trafficking microglia-like cells that reduce brain amyloid β

Han, Kyung Ho; Arlian, Britni M.; Macauley, Matthew; Paulson, James C.; Lerner, Richard A.

doi:10.1073/pnas.1719259115

Cited by 22 publications

(20 citation statements)

References 34 publications

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“…While the depletion of the entire microglia pool and repopulation by PDMCs is a good model to study myeloid cell dynamics in controlled experimental settings, it is most likely not a feasible therapeutic approach for patient populations. Nevertheless, recent research efforts into the recruitment of peripheral macrophages to the CNS have led to promising approaches to achieve significant engraftment of peripheral myeloid cells in the brain without the need for opening the blood brain barrier or depletion of endogenous microglia 45 . These efforts and the obvious importance of the innate immune response in AD progression 46 have pushed myeloid cell-based approaches into the spotlight of viable therapeutic options.…”

Section: Discussionmentioning

confidence: 99%

The Amyloid-beta rich CNS environment alters myeloid cell functionality independent of their origin

Drost

Houtman

Cseresnyés

et al. 2020

Sci Rep

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Microglia, the innate immune cells of the central nervous system (CNS) survey their surroundingswith their cytoplasmic processes, phagocytose debris and rapidly respond to injury. These functions are affected by the presence of beta-Amyloid (Aβ) deposits, hallmark lesions of Alzheimer's disease (AD). We recently demonstrated that exchanging functionally altered endogenous microglia with peripheral myeloid cells did not change Aβ-burden in a mouse model mimicking aspects of AD at baseline, and only mildly reduced Aβ plaques upon stimulation. To better characterize these different myeloid cell populations, we used long-term in vivo 2-photon microscopy to compare morphology and basic functional parameters of brain populating peripherally-derived myeloid cells and endogenous microglia. While peripherally-derived myeloid cells exhibited increased process movement in the nondiseased brain, the Aβ rich environment in an AD-like mouse model, which induced an alteration of surveillance functions in endogenous microglia, also restricted functional characteristics and response to CNS injury of newly recruited peripherally-derived myeloid cells. Our data demonstrate that the Aβ rich brain environment alters the functional characteristics of endogenous microglia as well as newly recruited peripheral myeloid cells, which has implications for the role of myeloid cells in disease and the utilization of these cells in Alzheimer's disease therapy.Dementia caused by Alzheimer's disease (AD) currently affects over 35 million people worldwide 1 and is characterized by extracellular deposition of beta-Amyloid (Aβ), intracellular neurofibrillary Tau tangles and neurodegeneration 2,3 . The identification of microglia associated genes as risk factors for sporadic AD has highlighted the importance of microglia, the intrinsic immune cells of the central nervous system (CNS), in the disease process 4,5 . In the healthy brain microglia are surveying their environment with their fine, arborizing cytoplasmic processes, screening the entire brain parenchyma every few hours and rapidly responding to injury 6 . As a resident cell population with limited turnover 7 microglia functionality as measured by baseline motility of cytoplasmic

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Section: Discussionmentioning

confidence: 99%

The Amyloid-beta rich CNS environment alters myeloid cell functionality independent of their origin

Drost

Houtman

Cseresnyés

et al. 2020

Sci Rep

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“…Proteins were then separated by SDS/PAGE and transferred to a membrane using the iBlot blotting system (Invitrogen, Carlsbad, CA, USA). IYD protein (Fitzgerald, North Action, MA, USA), IYD DNA (OriGene, Rockville, MD, USA), IYD shRNA (OriGene, Rockville, MD, USA), β actin, phospho-AKT, ERK, and p38 (Cell Signaling Technology, Danvers, MA, USA) were used for Western blotting as described previously [1].…”

Section: Western Blotmentioning

confidence: 99%

“…We have devised a method to isolate antibodies that control cell fates using intracellular combinatorial libraries in vitro [2,6,7]. Previously, a novel in vivo selection method was used to identify antibodies that induce hematopoietic stem cells to both differentiate into microglia and to selectively migrate to the brain [1]. Here, we studied ( Figure 1) an unbiased in vivo selection to identify an agonist antibody that induces bone marrow cells to traffic to the heart.…”

Section: In Vivo Selection Of Antibodies That Induce Cell Migrationmentioning

confidence: 99%

“…Recently, we discovered such a dual-function enzyme while studying intracellular combinatorial antibody libraries that regulate cell fates, particularly when autocrine selections are used [1][2][3][4][5][6]. We have previously applied this system to isolate antibodies capable of differentiating stem cells into specific immune cell types, of inserting functional proteins within proteins, and of serving as a fluorescent cell reporter to identify ligand and receptor interactions [1][2][3][4][5][6]. Here, we wanted to select antibodies that regulate migration of hematopoietic stem cells to peripheral tissues.…”

Section: Introductionmentioning

confidence: 99%

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Agonist Antibody Converts Stem Cells into Migrating Brown Adipocyte-Like Cells in Heart

Han

Arlian

Lin

et al. 2020

Cells

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We present data showing that Iodotyrosine Deiodinase (IYD) is a dual-function enzyme acting as a catalyst in metabolism and a receptor for cooperative stem cell differentiation. IYD is present both in thyroid cells where it is critical for scavenging iodine from halogenated by-products of thyroid hormone production and on hematopoietic stem cells. To close the cooperative loop, the mono- and di-Iodotyrosine (MIT and DIT) substrates of IYD in the thyroid are also agonists for IYD now acting as a receptor on bone marrow stem cells. While studying intracellular combinatorial antibody libraries, we discovered an agonist antibody, H3 Ab, of which the target is the enzyme IYD. When agonized by H3 Ab, IYD expressed on stem cells induces differentiation of the cells into brown adipocyte-like cells, which selectively migrate to mouse heart tissue. H3 Ab also binds to IYD expressed on human myocardium. Thus, one has a single enzyme acting in different ways on different cells for the cooperative purpose of enhancing thermogenesis or of regenerating damaged heart tissue.

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“…Han et al have developed an antibody that induces the differentiation of bone marrow cells into microglia cells that traffic to the brain where they self-organize into typical networks [ 128 ]. They created a human ScFv lentiviral intracellular combinatorial antibody library with 10 8 unique antibody clones.…”

Section: Stem Cells and Regenerative Medicinementioning

confidence: 99%

Neuro-Immuno-Gene- and Genome-Editing-Therapy for Alzheimer’s Disease: Are We There Yet?

Raikwar

Thangavel

Dubova

et al. 2018

JAD

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Alzheimer’s disease (AD) is a highly complex neurodegenerative disorder and the current treatment strategies are largely ineffective thereby leading to irreversible and progressive cognitive decline in AD patients. AD continues to defy successful treatment despite significant advancements in the field of molecular medicine. Repeatedly, early promising preclinical and clinical results have catapulted into devastating setbacks leading to multi-billion dollar losses not only to the top pharmaceutical companies but also to the AD patients and their families. Thus, it is very timely to review the progress in the emerging fields of gene therapy and stem cell-based precision medicine. Here, we have made sincere efforts to feature the ongoing progress especially in the field of AD gene therapy and stem cell-based regenerative medicine. Further, we also provide highlights in elucidating the molecular mechanisms underlying AD pathogenesis and describe novel AD therapeutic targets and strategies for the new drug discovery. We hope that the quantum leap in the scientific advancements and improved funding will bolster novel concepts that will propel the momentum toward a trajectory leading to a robust AD patient-specific next generation precision medicine with improved cognitive function and excellent life quality.

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Migration-based selections of antibodies that convert bone marrow into trafficking microglia-like cells that reduce brain amyloid β

Cited by 22 publications

References 34 publications

The Amyloid-beta rich CNS environment alters myeloid cell functionality independent of their origin

The Amyloid-beta rich CNS environment alters myeloid cell functionality independent of their origin

Agonist Antibody Converts Stem Cells into Migrating Brown Adipocyte-Like Cells in Heart

Neuro-Immuno-Gene- and Genome-Editing-Therapy for Alzheimer’s Disease: Are We There Yet?

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