Brain conditioning is instrumental for successful microglia reconstitution following hematopoietic stem cell transplantation

Capotondo, Alessia; Milazzo, Rita; Politi, Letterio S.; Quattrini, Angelo; Palini, Alessio; Plati, Tiziana; Merella, Stefania; Nonis, Alessandro; Serio, Clelia Di; Montini, Eugenio; Naldini, Luigi; Biffi, Alessandra

doi:10.1073/pnas.1205858109

Cited by 178 publications

(208 citation statements)

References 28 publications

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“…To assess tumorigenic potential, DIV 4-induced TH-GFP + cells were FACS sorted, replated, and transplanted the following day into 3-weekold immunodeficient Rag2 -/-Ilrg tmWjl -null mice, a strain that efficiently supports xenograft survival with particular sensitivity to rare tumorigenic cells (41). At 5 and 12 weeks after transplantation of about 5 × 10 5 iDA neurons (n = 10), we tested the integration and proliferation of the grafted cells.…”

Section: Resultsmentioning

confidence: 99%

Remote control of induced dopaminergic neurons in parkinsonian rats

et al. 2014

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Direct lineage reprogramming through genetic-based strategies enables the conversion of differentiated somatic cells into functional neurons and distinct neuronal subtypes. Induced dopaminergic (iDA) neurons can be generated by direct conversion of skin fibroblasts; however, their in vivo phenotypic and functional properties remain incompletely understood, leaving their impact on Parkinson's disease (PD) cell therapy and modeling uncertain. Here, we determined that iDA neurons retain a transgene-independent stable phenotype in culture and in animal models. Furthermore, transplanted iDA neurons functionally integrated into host neuronal tissue, exhibiting electrically excitable membranes, synaptic currents, dopamine release, and substantial reduction of motor symptoms in a PD animal model. Neuronal cell replacement approaches will benefit from a system that allows the activity of transplanted neurons to be controlled remotely and enables modulation depending on the physiological needs of the recipient; therefore, we adapted a DREADD (designer receptor exclusively activated by designer drug) technology for remote and real-time control of grafted iDA neuronal activity in living animals. Remote DREADD-dependent iDA neuron activation markedly enhanced the beneficial effects in transplanted PD animals. These data suggest that iDA neurons have therapeutic potential as a cell replacement approach for PD and highlight the applicability of pharmacogenetics for enhancing cellular signaling in reprogrammed cell-based approaches.

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Section: Resultsmentioning

confidence: 99%

Remote control of induced dopaminergic neurons in parkinsonian rats

et al. 2014

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“…First, parameters such as morphology or CD45 expression may change with disease or injury. Second, chimeric mouse generation leads to partial chimerism, causes inflammatory damage, and can take many months (8,9). More recently, tools based on microglial expression of the fractalkine receptor, Cx3cr1, overcame some of these limitations.…”

mentioning

confidence: 99%

New tools for studying microglia in the mouse and human CNS

Bennett

Liddelow

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

1,468

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The specific function of microglia, the tissue resident macrophages of the brain and spinal cord, has been difficult to ascertain because of a lack of tools to distinguish microglia from other immune cells, thereby limiting specific immunostaining, purification, and manipulation. Because of their unique developmental origins and predicted functions, the distinction of microglia from other myeloid cells is critically important for understanding brain development and disease; better tools would greatly facilitate studies of microglia function in the developing, adult, and injured CNS. Here, we identify transmembrane protein 119 (Tmem119), a cell-surface protein of unknown function, as a highly expressed microglia-specific marker in both mouse and human. We developed monoclonal antibodies to its intracellular and extracellular domains that enable the immunostaining of microglia in histological sections in healthy and diseased brains, as well as isolation of pure nonactivated microglia by FACS. Using our antibodies, we provide, to our knowledge, the first RNAseq profiles of highly pure mouse microglia during development and after an immune challenge. We used these to demonstrate that mouse microglia mature by the second postnatal week and to predict novel microglial functions. Together, we anticipate these resources will be valuable for the future study and understanding of microglia in health and disease.

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“…Consistently, Capotondo et al demonstrated that hematopoietic stem cell transplantation in a non-disease state of the host mice resulted in a short-term of cell infiltration into the brain. However, ablation of brain-resident myeloid precursors via busulfan treatment caused the long-term turnover of CNS microglia by the engrafted bone marrow-derived cells [114]. Following kainic acid administration with BU and cyclophosphamide treatment, circulating monocytes physiologically engrafted the brain and gave rise to activated macrophages [115].…”

Section: Pathological Conditions and Chemotherapies Induce The Infiltmentioning

confidence: 99%

Friend or Foe? Resident Microglia vs Bone Marrow-Derived Microglia and Their Roles in the Retinal Degeneration

et al. 2016

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Microglia are immune cells in the central nervous system (CNS) that originate from the yolk sac in an embryo. The renewal of the microglia pool in the adult eye consists of two components. In addition to the self-proliferation of resident cells, microglia in the CNS also derive from the bone marrow (BM). BM-derived cells pass through the blood-brain barrier (BBB) or blood-retina barrier (BRB) and differentiate into microglia under specific conditions which involves a complex mechanism. Recent studies have widely investigated the role of resident microglia and BM-derived microglia in the retinal degenerative disease. Both two cell types play dual roles and share many similar functions. However, resident microglia tend to polarize to the M1 phenotype which is pro-inflammatory and neurotoxic, whereas BM-derived microglia mainly polarize to the neuroprotective M2 phenotype in retinal degeneration. The molecular mechanism that underlines the invasion of peripheral cells has led to extensive discussions. In addition to the BBB and BRB disruption, many signaling pathways are involved in this process. Based on these studies, we discuss the roles of these two types of microglia in retinal degeneration disease and the potential clinical application of BM-derived microglia, which may benefit future therapies.

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Brain conditioning is instrumental for successful microglia reconstitution following hematopoietic stem cell transplantation

Cited by 178 publications

References 28 publications

Remote control of induced dopaminergic neurons in parkinsonian rats

Remote control of induced dopaminergic neurons in parkinsonian rats

New tools for studying microglia in the mouse and human CNS

Friend or Foe? Resident Microglia vs Bone Marrow-Derived Microglia and Their Roles in the Retinal Degeneration

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