Mapping the Fine-Scale Organization and Plasticity of the Brain Vasculature

Kirst, Christoph; Skriabine, Sophie; Vieites‐Prado, Alba; Topilko, Thomas; Bertin, Paul; Gerschenfeld, Gaspard; Verny, Florine; Topilko, Piotr; Michalski, Nicolas; Tessier‐Lavigne, Marc; Renier, Nicolas

doi:10.1016/j.cell.2020.01.028

Cited by 298 publications

(370 citation statements)

References 78 publications

(97 reference statements)

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“…To ensure correct alignment between channels, we applied a series of rigid and non-rigid registration steps using the Elastix toolbox (Klein et al, 2010) to map the Cux1 and Ctip2 channels onto the TO-PRO-3 channel without inducing non-specific local background warping ( Figure S1). We also found that many of the commonly used programs for performing 3D image stitching (Bria and Iannello, 2012;Hörl et al, 2019) did not accurately align adjacent tile stacks due to spurious stage movement, which has been noted by other groups (Kirst et al, 2020). To ensure accurate image reconstruction, we applied a simplified iterative 2D stitching procedure that uses scale-invariant feature transforms (Lowe, 2004) to produce continuous images without cell duplication along tile edges ( Figure S2).…”

Section: Results Idisco+ Reveals Neuronal Cell-type Deficits In the Tmentioning

confidence: 99%

NuMorph: tools for cellular phenotyping in tissue cleared whole brain images

Krupa

Fragola

Hadden-Ford

et al. 2020

Preprint

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Tissue clearing methods allow every cell in the mouse brain to be imaged without physical sectioning. However, the computational tools currently available for cell quantification in cleared tissue images have been limited to counting sparse cell populations in stereotypical mice. Here we introduce NuMorph, a group of image analysis tools to quantify all nuclei and nuclear markers within the mouse cortex after tissue clearing and imaging by a conventional light-sheet microscope. We applied NuMorph to investigate a Topoisomerase 1 (Top1) conditional knockout mouse model with severe brain structure deficits and identified differential effects of Top1 deletion on cortical cell-types and structures that were associated with spatial patterns of long gene expression. These tools are applicable for the study of 3D cellular level structural deficits in brains from other animal models of neuropsychiatric disorders.

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Section: Results Idisco+ Reveals Neuronal Cell-type Deficits In the Tmentioning

confidence: 99%

NuMorph: tools for cellular phenotyping in tissue cleared whole brain images

Krupa

Fragola

Hadden-Ford

et al. 2020

Preprint

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“…In the harmine-exendin-4-treated mice (red line), beta cell volume remains stable during the first month and increases markedly by the end of month 3. Since beta cell mass declines markedly in the first day or days following transplant (8,9), the actual course of events likely resembles the dotted green line. B.…”

Section: Methodsmentioning

confidence: 99%

“…We have used adult human cadaveric islets transplanted into the kidney capsule of immunodeficient NOD-SCID-gamma (NSG) mice (1-3), followed by chronic treatment with a DYRK1A inhibitor (harmine) alone or in combination with a widely used GLP1RA peptide (exendin-4) over one to three months. We have combined this standard animal model with advanced iDISCO + tissue clearing, light-sheet microscopy and 3-D image rendering techniques to quantify human beta cell mass (7,8). We find that harmine and exendin-4 co-administration increases human beta cell mass by a factor of 7fold over three months, without significant alterations in alpha cell mass.…”

Section: Introductionmentioning

confidence: 99%

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Human Beta Cell Mass Expansion In Vivo With A Harmine and Exendin-4 Combination: Quantification and Visualization By iDISCO+ 3D Imaging

Rosselot

Alvarsson

Wang

et al. 2020

Preprint

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Since all diabetes results from reductions in numbers of functional pancreatic beta cells, beta cell regenerative drugs are required for optimal and scalable future diabetes treatment. While many diabetes drugs are in clinical use, none increases human beta cell numbers. We have shown that a combination of the DYRK1A inhibitor, harmine, with the GLP1 receptor agonist, exendin-4, markedly increases human beta cell proliferation in vitro. However, technological limitations have prevented assessment of human beta cell mass in vivo. Here, we describe a novel method that combines iDISCO+ tissue clearing, insulin immunolabeling, light sheet microscopy, and volumetric quantification of human beta cells transplanted into immunodeficient mice. We demonstrate a striking seven-fold in vivo increase in human beta cell mass in response to three months of combined harmine-exendin-4 combination infusion, accompanied by lower blood glucose levels, increased plasma human insulin concentrations and enhanced beta cell proliferation. These studies unequivocally demonstrate for the first time that pharmacologic human beta cell expansion is a realistic and achievable path to diabetes therapy, and provide a rigorous, entirely novel and reproducible tool for quantifying human beta cell mass in vivo.

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“…Recent advancements in tissue clearing technology have brought new breakthroughs in this landscape [1,2,3,4,5,6,7,8,9]. Combined with light-sheet fluorescence microscopy (LSFM) [10] and genetical, viral and immunohistochemical labelling techniques, tissue clearing now enables high-speed volumetric imaging of mammalian (most prominently mouse) brains at cellular resolution [7,11,12,13,14,15,16,17]. Built on top of these technological advancements, we recently reported the construction of CUBIC-Atlas [18], a 3D mouse brain atlas with single cell resolution, where all of the cells in the brain (amounting to approximately 0.1 billion) were digitally analyzed and recorded.…”

Section: Introductionmentioning

confidence: 99%

CUBIC-Cloud: An Integrative Computational Framework Towards Community-driven Whole-Mouse-Brain Mapping

Mano

Murata

Kon

et al. 2020

Preprint

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Recent advancements in tissue clearing technologies have offered unparalleled opportunities for researchers to explore the whole mouse brain at cellular resolution. With the expansion of this experimental technique, however, a scalable and easy-to-use computational tool is in demand to effectively analyze and integrate whole-brain mapping datasets. To that end, here we present CUBIC-Cloud, a cloud-based framework to quantify, visualize and integrate whole mouse brain data. CUBIC-Cloud is a fully automated system where users can upload their whole-brain data, run analysis and publish the results. We demonstrate the generality of CUBIC-Cloud by a variety of applications. First, we investigated brain-wide distribution of PV, Sst, ChAT, Th and Iba1 expressing cells. Second, Aβ plaque deposition in AD model mouse brains were quantified. Third, we reconstructed neuronal activity profile under LPS-induced inflammation by c-Fos immunostaining. Last, we show brain-wide connectivity mapping by pseudo-typed Rabies virus. Together, CUBIC-Cloud provides an integrative platform to advance scalable and collaborative whole-brain mapping.

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Mapping the Fine-Scale Organization and Plasticity of the Brain Vasculature

Cited by 298 publications

References 78 publications

NuMorph: tools for cellular phenotyping in tissue cleared whole brain images

NuMorph: tools for cellular phenotyping in tissue cleared whole brain images

Human Beta Cell Mass Expansion In Vivo With A Harmine and Exendin-4 Combination: Quantification and Visualization By iDISCO+ 3D Imaging

CUBIC-Cloud: An Integrative Computational Framework Towards Community-driven Whole-Mouse-Brain Mapping

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