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1. PICALM Rescues Endocytic Defects Caused by the Alzheimer’s Disease Risk Factor APOE4

Author

Priyanka Narayan, Grzegorz Sienski, Julia M. Bonner, Yuan-Ta Lin, Jinsoo Seo, Valeriya Baru, Aftabul Haque, Blerta Milo, Leyla A. Akay, Agnese Graziosi, Yelena Freyzon, Dirk Landgraf, William R. Hesse, Julie Valastyan, M. Inmaculada Barrasa, Li-Huei Tsai, and Susan Lindquist

Subjects
apolipoprotein E, Alzheimer's disease, genetic risk factors, PICALM, endocytosis, trafficking, Biology (General), QH301-705.5
Abstract

Summary: The ε4 allele of apolipoprotein E (APOE4) is a genetic risk factor for many diseases, including late-onset Alzheimer’s disease (AD). We investigate the cellular consequences of APOE4 in human iPSC-derived astrocytes, observing an endocytic defect in APOE4 astrocytes compared with their isogenic APOE3 counterparts. Given the evolutionarily conserved nature of endocytosis, we built a yeast model to identify genetic modifiers of the endocytic defect associated with APOE4. In yeast, only the expression of APOE4 results in dose-dependent defects in both endocytosis and growth. We discover that increasing expression of the early endocytic adaptor protein Yap1802p, a homolog of the human AD risk factor PICALM, rescues the APOE4-induced endocytic defect. In iPSC-derived human astrocytes, increasing expression of PICALM similarly reverses endocytic disruptions. Our work identifies a functional interaction between two AD genetic risk factors—APOE4 and PICALM—centered on the conserved biological process of endocytosis.

Published
2020
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2. Distinct effects of disease-associated TREM2 R47H/+ and T66M mutations on iPSC-derived microglia

Author

Jay Penney, William T Ralvenius, Anjanet Loon, Oyku Cerit, Vishnu Dileep, Blerta Milo, Hannah Woolf, and Li-Huei Tsai

Abstract

Genetic findings have highlighted key roles for microglia in the pathology of neurodegenerative conditions such as Alzheimer’s disease (AD). Distinct mutations in the microglial protein TREM2 (triggering receptor expressed on myeloid cells 2) are associated with different forms of neurodegeneration in humans; R47H/+ mutations increase AD risk, while loss-of-function mutations such as TREM2 T66M result in more severe forms of neurodegeneration. We employed gene editing and stem cell models to gain insight into the effects of these mutations on human iPSC-derived microglia. We found divergent effects of TREM2 R47H/+ and T66M mutations on gene expression, with R47H/+ cells exhibiting a pro-inflammatory gene expression signature. Both the TREM2 R47H/+ and T66M mutations caused similar impairments in microglial movement and the uptake of multiple substrates, while R47H/+ microglia were hyper-responsive to inflammatory stimuli, consistent with their gene expression signature. We developed an in vitro laser-induced injury model in neuron-microglia co-cultures, finding an impaired injury response by TREM2 R47H/+ microglia. Furthermore, in xenotransplantation experiments, mouse brains transplanted with TREM2 R47H/+ microglia exhibited reduced synaptic density. Consistently, we observed upregulation of multiple complement cascade components in TREM2 R47H/+ microglia, suggesting that inappropriate synaptic pruning may underlie the effect. Thus, these findings identify shared and distinct effects of these two TREM2 mutations on microglial gene expression and function. While the TREM2 T66M mutation impairs microglial movement and uptake processes, the TREM2 R47H/+ mutation additionally confers multiple potentially detrimental effects on human microglia, likely to underlie its association with AD.

Published
2022
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3. APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia

Author

Leyla Anne Akay, Susan Lindquist, Agnese Graziosi, Sebastian Boland, William T. Ralvenius, Valeriya Baru, Aleksandra Alicja Arczewska, Nora Kory, Julia Maeve Bonner, Elana Lockshin, Grzegorz Sienski, Caroline A. Lewis, Priyanka Narayan, Blerta Milo, Manolis Kellis, Liang He, David M. Sabatini, Li-Huei Tsai, Sienski G., Narayan P., Bonner J.M., Kory N., Boland S., Arczewska A.A., Ralvenius W.T., Akay L., Lockshin E., He L., Milo B., Graziosi A., Baru V., Lewis C.A., Kellis M., Sabatini D.M., Tsai L.-H., and Lindquist S.

Subjects
Apolipoprotein E, Lipid metabolism, General Medicine, Lipidome, Biology, Article, Cell biology, medicine.anatomical_structure, Lipid droplet, Lipidomics, mental disorders, medicine, Neuroglia, lipids (amino acids, peptides, and proteins), human activities, Lipid Transport, Intracellular, alzheimer apoe4 apoe3 iPSCs lipid glia
Abstract

Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works The E4 allele of the apolipoprotein E gene (APOE) has been established as a genetic risk factor for many diseases including cardiovascular diseases and Alzheimer’s disease (AD), yet its mechanism of action remains poorly understood. APOE is a lipid transport protein, and the dysregulation of lipids has recently emerged as a key feature of several neurodegenerative diseases including AD. However, it is unclear how APOE4 perturbs the intracellular lipid state. Here, we report that APOE4, but not APOE3, disrupted the cellular lipidomes of human induced pluripotent stem cell (iPSC)–derived astrocytes generated from fibroblasts of APOE4 or APOE3 carriers, and of yeast expressing human APOE isoforms. We combined lipidomics and unbiased genome-wide screens in yeast with functional and genetic characterization to demonstrate that human APOE4 induced altered lipid homeostasis. These changes resulted in increased unsaturation of fatty acids and accumulation of intracellular lipid droplets both in yeast and in APOE4-expressing human iPSC-derived astrocytes. We then identified genetic and chemical modulators of this lipid disruption. We showed that supplementation of the culture medium with choline (a soluble phospholipid precursor) restored the cellular lipidome to its basal state in APOE4-expressing human iPSC-derived astrocytes and in yeast expressing human APOE4. Our study illuminates key molecular disruptions in lipid metabolism that may contribute to the disease risk linked to the APOE4 genotype. Our study suggests that manipulating lipid metabolism could be a therapeutic approach to help alleviate the consequences of carrying the APOE4 allele.

Published
2021

4. PICALM Rescues Endocytic Defects Caused by the Alzheimer’s Disease Risk Factor APOE4

Author

Julia Maeve Bonner, Susan Lindquist, Leyla Anne Akay, M. Inmaculada Barrasa, Julie S. Valastyan, Agnese Graziosi, Valeriya Baru, Aftabul Haque, Yelena Freyzon, Grzegorz Sienski, William R. Hesse, Li-Huei Tsai, Priyanka Narayan, Yuan-Ta Lin, Jinsoo Seo, Blerta Milo, and Dirk Landgraf

Subjects
0301 basic medicine, Apolipoprotein E, Endocytic cycle, Apolipoprotein E4, Biology, Endocytosis, General Biochemistry, Genetics and Molecular Biology, Article, PICALM, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Risk Factors, trafficking, mental disorders, genetic risk factors, Humans, endocytosis, Allele, Induced pluripotent stem cell, lcsh:QH301-705.5, apolipoprotein E, Signal transducing adaptor protein, Alzheimer's disease, Cell biology, 030104 developmental biology, lcsh:Biology (General), lipids (amino acids, peptides, and proteins), Stem cell, human activities, 030217 neurology & neurosurgery
Abstract

Summary: The ε4 allele of apolipoprotein E (APOE4) is a genetic risk factor for many diseases, including late-onset Alzheimer’s disease (AD). We investigate the cellular consequences of APOE4 in human iPSC-derived astrocytes, observing an endocytic defect in APOE4 astrocytes compared with their isogenic APOE3 counterparts. Given the evolutionarily conserved nature of endocytosis, we built a yeast model to identify genetic modifiers of the endocytic defect associated with APOE4. In yeast, only the expression of APOE4 results in dose-dependent defects in both endocytosis and growth. We discover that increasing expression of the early endocytic adaptor protein Yap1802p, a homolog of the human AD risk factor PICALM, rescues the APOE4-induced endocytic defect. In iPSC-derived human astrocytes, increasing expression of PICALM similarly reverses endocytic disruptions. Our work identifies a functional interaction between two AD genetic risk factors—APOE4 and PICALM—centered on the conserved biological process of endocytosis.

Published
2020

5. F1‐07‐04: USING HUMAN IPSC MODELS TO PROBE TREM2 FUNCTION

Author

Blerta Milo, Fan Gao, Jay Penney, Sara Elmsaouri, and Li-Huei Tsai

Subjects
Physics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Function (mathematics), Geriatrics and Gerontology, Biological system
Published
2019
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6. Physicochemical characterization of ferumoxytol, heparin and protamine nanocomplexes for improved magnetic labeling of stem cells

Author

L. Henry Bryant, Blerta Milo, Richard D. Leapman, Saejeong J. Kim, Neekita Jikaria, Zsofia I. Kovacs, Maria A. Aronova, Alioscka A. Sousa, Bobbi K. Lewis, Joseph A. Frank, Guofeng Zhang, and Matthew Hobson

Subjects
Materials science, Cell, Biomedical Engineering, Protamine, Pharmaceutical Science, Medicine (miscellaneous), Bioengineering, Stem cells, 02 engineering and technology, Regenerative medicine, Article, 030218 nuclear medicine & medical imaging, Magnetics, 03 medical and health sciences, 0302 clinical medicine, Nuclear magnetic resonance, medicine, Humans, General Materials Science, Protamines, Ferumoxytol, biology, Heparin, Stem Cells, Mesenchymal stem cell, 021001 nanoscience & nanotechnology, Magnetic Resonance Imaging, Ferrosoferric Oxide, Neural stem cell, medicine.anatomical_structure, Cell Tracking, biology.protein, Biophysics, Nanoparticles, Molecular Medicine, Stem cell, 0210 nano-technology, Stem Cell Transplantation, Cell labeling, medicine.drug
Abstract

Intramural Research Program of the Clinical Center at the National Institutes of Health Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering at the National Institutes of Health Stem cell-based therapies have become a major focus in regenerative medicine and to treat diseases. A straightforward approach combining three drugs, heparin (H), protamine (P) with ferumoxytol (F) in the form of nanocomplexes (NCs) effectively labeled stem cells for cellular MRI. We report on the physicochemical characteristics for optimizing the H, P, and F components in different ratios, and mixing sequences, producing NCs that varied in hydrodynamic size. NC size depended on the order in which drugs were mixed in media. Electron microscopy of HPF or FHP showed that F was located on the surface of spheroidal shaped HP complexes. Human stem cells incubated with FHP NCs resulted in a significantly greater iron concentration per cell compared to that found in HPF NCs with the same concentration of F. These results indicate that FHP could be useful for labeling stem cells in translational studies in the clinic. Published by Elsevier Inc. Ctr Clin, Lab Diagnost Radiol Res Radiol & Imaging Sci, Bethesda, MD USA NIH, Frank Lab Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD USA Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA Univ Fed Sao Paulo, Dept Biochem, Sao Paulo, Brazil Univ Fed Sao Paulo, Dept Biochem, Sao Paulo, Brazil Web of Science

Published
2017
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7. International Society for Therapeutic Ultrasound Conference 2016

Author

Brian Fowlkes, Pejman Ghanouni, Narendra Sanghvi, Constantin Coussios, Paul C. Lyon, Michael Gray, Christophoros Mannaris, Marie de Saint Victor, Eleanor Stride, Robin Cleveland, Robert Carlisle, Feng Wu, Mark Middleton, Fergus Gleeson, Jean-Franҫois Aubry, Kim Butts Pauly, Chrit Moonen, Jacob Vortman, Shirley Sharabi, Dianne Daniels, David Last, David Guez, Yoav Levy, Alexander Volovick, Javier Grinfeld, Itay Rachmilevich, Talia Amar, Zion Zibly, Yael Mardor, Sagi Harnof, Michael Plaksin, Yoni Weissler, Shy Shoham, Eitan Kimmel, Omer Naor, Nairouz Farah, Dong-Guk Paeng, Zhiyuan Xu, John Snell, Anders H. Quigg, Matthew Eames, Changzhu Jin, Ashli C. Everstine, Jason P. Sheehan, Beatriz S. Lopes, Neal Kassell, Thomas Looi, Vera Khokhlova, Charles Mougenot, Kullervo Hynynen, James Drake, Michael Slayton, Richard C. Amodei, Keegan Compton, Ashley McNelly, Daniel Latt, John Kearney, David Melodelima, Aurelien Dupre, Yao Chen, David Perol, Jeremy Vincenot, Jean-Yves Chapelon, Michel Rivoire, Wei Guo, Guoxin Ren, Guofeng Shen, Michael Neidrauer, Leonid Zubkov, Michael S. Weingarten, David J. Margolis, Peter A. Lewin, Nathan McDannold, Jonathan Sutton, Natalia Vykhodtseva, Margaret Livingstone, Thiele Kobus, Yong-Zhi Zhang, Michael Schwartz, Yuexi Huang, Nir Lipsman, Jennifer Jain, Martin Chapman, Tejas Sankar, Andres Lozano, Robert Yeung, Christakis Damianou, Nikolaos Papadopoulos, Omer Brokman, Eyal Zadicario, Ori Brenner, David Castel, Shih-Ying Wu, Julien Grondin, Wenlan Zheng, Marc Heidmann, Maria Eleni Karakatsani, Carlos J. Sierra Sánchez, Vincent Ferrera, Elisa E. Konofagou, Marinos Yiannakou, HongSeok Cho, Hwayoun Lee, Mun Han, Jong-Ryul Choi, Taekwan Lee, Sanghyun Ahn, Yongmin Chang, Juyoung Park, Nicholas Ellens, Ari Partanen, Keyvan Farahani, Raag Airan, Alexandre Carpentier, Michael Canney, Alexandre Vignot, Cyril Lafon, Jean-yves Delattre, Ahmed Idbaih, Henrik Odéen, Bradley Bolster, Eun Kee Jeong, Dennis L. Parker, Pooja Gaur, Xue Feng, Samuel Fielden, Craig Meyer, Beat Werner, William Grissom, Michael Marx, Hans Weber, Valentina Taviani, Brian Hargreaves, Jun Tanaka, Kentaro Kikuchi, Ayumu Ishijima, Takashi Azuma, Kosuke Minamihata, Satoshi Yamaguchi, Teruyuki Nagamune, Ichiro Sakuma, Shu Takagi, Mathieu D. Santin, Laurent Marsac, Guillaume Maimbourg, Morgane Monfort, Benoit Larrat, Chantal François, Stéphane Lehéricy, Mickael Tanter, Gesthimani Samiotaki, Shutao Wang, Camilo Acosta, Eliza R. Feinberg, Zsofia I. Kovacs, Tsang-Wei Tu, Georgios Z. Papadakis, William C. Reid, Dima A. Hammoud, Joseph A. Frank, Zsofia i. Kovacs, Saejeong Kim, Neekita Jikaria, Michele Bresler, Farhan Qureshi, Jingjing Xia, Po-Shiang Tsui, Hao-Li Liu, Juan C. Plata, Bragi Sveinsson, Vasant A. Salgaonkar, Matthew Adams, Chris Diederich, Eugene Ozhinsky, Matthew D. Bucknor, Viola Rieke, Andrew Mikhail, Lauren Severance, Ayele H. Negussie, Bradford Wood, Martijn de Greef, Gerald Schubert, Mario Ries, Megan E. Poorman, Mary Dockery, Vandiver Chaplin, Stephanie O. Dudzinski, Ryan Spears, Charles Caskey, Todd Giorgio, Marcia M. Costa, Efthymia Papaevangelou, Anant Shah, Ian Rivens, Carol Box, Jeff Bamber, Gail ter Haar, Scott R. Burks, Matthew Nagle, Ben Nguyen, Blerta Milo, Nhan M. Le, Shaozhen Song, Kanheng Zhou, Ghulam Nabi, Zhihong Huang, Shmuel Ben-Ezra, Shani Rosen, Senay Mihcin, Jan Strehlow, Ioannis Karakitsios, Nhan Le, Michael Schwenke, Daniel Demedts, Paul Prentice, Sabrina Haase, Tobias Preusser, Andreas Melzer, Jean-Louis Mestas, Kamel Chettab, Gustavo Stadthagen Gomez, Charles Dumontet, Bettina Werle, Fabrice Marquet, Pierre Bour, Fanny Vaillant, Sana Amraoui, Rémi Dubois, Philippe Ritter, Michel Haïssaguerre, Mélèze Hocini, Olivier Bernus, Bruno Quesson, Amit Livneh, Dan Adam, Justine Robin, Bastien Arnal, Mathias Fink, Mathieu Pernot, Tatiana D. Khokhlova, George R. Schade, Yak-Nam Wang, Wayne Kreider, Julianna Simon, Frank Starr, Maria Karzova, Adam Maxwell, Michael R. Bailey, Jonathan E. Lundt, Steven P. Allen, Jonathan R. Sukovich, Timothy Hall, Zhen Xu, Philip May, Daniel W. Lin, Charlotte Constans, Thomas Deffieux, Jean-Francois Aubry, Eun-Joo Park, Yun Deok Ahn, Soo Yeon Kang, Dong-Hyuk Park, Jae Young Lee, J. Vidal-Jove, E. Perich, A. Ruiz, A. Jaen, N. Eres, M. Alvarez del Castillo, Rachel Myers, James Kwan, Christian Coviello, Cliff Rowe, Calum Crake, Sean Finn, Edward Jackson, Antonios Pouliopoulos, Caiqin Li, Marc Tinguely, Meng-Xing Tang, Valeria Garbin, James J. Choi, Lisa Folkes, Michael Stratford, Sandra Nwokeoha, Tong Li, Navid Farr, Samantha D’Andrea, Kayla Gravelle, Hong Chen, Donghoon Lee, Joo Ha Hwang, Sophie Tardoski, Jacqueline Ngo, Evelyne Gineyts, Jean-Pau Roux, Philippe Clézardin, Allegra Conti, Rémi Magnin, Matthieu Gerstenmayer, François Lux, Olivier Tillement, Sébastien Mériaux, Stefania Della Penna, Gian Luca Romani, Erik Dumont, Tao Sun, Chanikarn Power, Eric Miller, Oleg Sapozhnikov, Sergey Tsysar, Petr V. Yuldashev, Victor Svet, Dongli Li, Antonio Pellegrino, Nik Petrinic, Clive Siviour, Antoine Jerusalem, Peter V. Yuldashev, Bryan W. Cunitz, Barbrina Dunmire, Claude Inserra, Matthieu Guedra, Cyril Mauger, Bruno Gilles, Maxim Solovchuk, Tony W. H. Sheu, Marc Thiriet, Yufeng Zhou, Esra Neufeld, Christian Baumgartner, Davnah Payne, Adamos Kyriakou, Niels Kuster, Xu Xiao, Helen McLeod, Christopher Dillon, Allison Payne, Vera A. Khokhova, Ilya Sinilshchikov, Yulia Andriyakhina, Andrey Rybyanets, Natalia Shvetsova, Alex Berkovich, Igor Shvetsov, Caroline J. Shaw, John Civale, Dino Giussani, Christoph Lees, Valery Ozenne, Solenn Toupin, Vasant Salgaonkar, Elena Kaye, Sebastien Monette, Majid Maybody, Govindarajan Srimathveeravalli, Stephen Solomon, Amitabh Gulati, Mario Bezzi, Jürgen W. Jenne, Thomas Lango, Michael Müller, Giora Sat, Christine Tanner, Stephan Zangos, Matthias Günther, Au Hoang Dinh, Emilie Niaf, Flavie Bratan, Nicolas Guillen, Rémi Souchon, Carole Lartizien, Sebastien Crouzet, Olivier Rouviere, Yang Han, Thomas Payen, Carmine Palermo, Steve Sastra, Kenneth Olive, Johanna M. van Breugel, Maurice A. van den Bosch, Benjamin Fellah, Denis Le Bihan, Luis Hernandez-Garcia, Charles A. Cain, Erasmia Lyka, Delphine Elbes, Chunhui Li, Satoshi Tamano, Hayato Jimbo, Shin Yoshizawa, Keisuke Fujiwara, Kazunori Itani, Shin-ichiro Umemura, Dan Stoianovici, Zulfadhli Zaini, Ryo Takagi, Shenyan Zong, Ron Watkins, Aurea Pascal-Tenorio, Peter Jones, Kim Butts-Pauly, Donna Bouley, Yazhu Chen, Chung-Yin Lin, Han-Yi Hsieh, Kuo-Chen Wei, Camille Garnier, Gilles Renault, Reza Seifabadi, Emmanuel Wilson, Avinash Eranki, Peter Kim, Dennis Lübke, Peter Huber, Joachim Georgii, Caroline V. Dresky, Julian Haller, Pavel Yarmolenko, Karun Sharma, Haydar Celik, Guofeng Li, Weibao Qiu, Hairong Zheng, Meng-Yen Tsai, Po-Chun Chu, Taylor Webb, Urvi Vyas, Matthew Walker, Jidan Zhong, Adam C. Waspe, Mojgan Hodaie, Feng-Yi Yang, Sin-Luo Huang, Yuval Zur, Benny Assif, Christian Aurup, Hermes Kamimura, Antonio A. Carneiro, Sven Rothlübbers, Julia Schwaab, Graeme Houston, Haim Azhari, Noam Weiss, Jacob Sosna, S. Nahum Goldberg, Victor Barrere, Kee W. Jang, Bobbi Lewis, Xiaotong Wang, Visa Suomi, David Edwards, Zahary Larrabee, Arik Hananel, Boaz Rafaely, Rasha Elaimy Debbiny, Carmel Zeltser Dekel, Michael Assa, George Menikou, Petros Mouratidis, José A. Pineda-Pardo, Marta Del Álamo de Pedro, Raul Martinez, Frida Hernandez, Silvia Casas, Carlos Oliver, Patricia Pastor, Lidia Vela, Jose Obeso, Paul Greillier, Ali Zorgani, Stefan Catheline, Vyacheslav Solovov, Michael O. Vozdvizhenskiy, Andrew E. Orlov, Chueh-Hung Wu, Ming-Kuan Sun, Tiffany T. Shih, Wen-Shiang Chen, Fabrice Prieur, Arnaud Pillon, Valerie Cartron, Patrick Cebe, Nathalie Chansard, Maxime Lafond, Pauline Muleki Seya, Jean-Christophe Bera, Tanguy Boissenot, Elias Fattal, Alexandre Bordat, Helene Chacun, Claire Guetin, Nicolas Tsapis, Kazuo Maruyama, Johan Unga, Ryo Suzuki, Cécile Fant, Bernadette Rogez, Mercy Afadzi, Ola Finneng Myhre, Siri Vea, Astrid Bjørkøy, Petros Tesfamichael Yemane, Annemieke van Wamel, Sigrid Berg, Rune Hansen, Bjørn Angelsen, and Catharina Davies

Subjects
0301 basic medicine, medicine.medical_specialty, Therapeutic ultrasound, business.industry, Tel aviv, medicine.medical_treatment, 02 engineering and technology, 021001 nanoscience & nanotechnology, 03 medical and health sciences, 030104 developmental biology, Ophthalmology, medicine, Radiology, Nuclear Medicine and imaging, Medical physics, 0210 nano-technology, business
Published
2017
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8. Improving the therapeutic efficacy of mesenchymal stromal cells to restore perfusion in critical limb ischemia through pulsed focused ultrasound

Author

Scott R. Burks, Victor Frenkel, Joseph A. Frank, Rashida A. Williams, Blerta Milo, Saejeong J. Kim, and Pamela Tebebi

Subjects
Proteomics, Vascular Endothelial Growth Factor A, 0301 basic medicine, CD31, medicine.medical_specialty, Proteome, Inflammation, Mesenchymal Stem Cell Transplantation, Article, Mice, 03 medical and health sciences, chemistry.chemical_compound, Ischemia, Fibrosis, medicine, Animals, Ultrasonography, Doppler, Color, Muscle, Skeletal, Multidisciplinary, business.industry, Mesenchymal stem cell, Skeletal muscle, Extremities, Mesenchymal Stem Cells, medicine.disease, Interleukin-10, Vascular endothelial growth factor, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Ultrasonic Waves, chemistry, Reperfusion, Cancer research, Female, Radiology, medicine.symptom, business, Perfusion, Biomarkers, Homing (hematopoietic)
Abstract

Mesenchymal stem cells (MSC) are promising therapeutics for critical limb ischemia (CLI). Mechanotransduction from pulsed focused ultrasound (pFUS) upregulates local chemoattractants to enhance homing of intravenously (IV)-infused MSC and improve outcomes. This study investigated whether pFUS exposures to skeletal muscle would improve local homing of iv-infused MSCs and their therapeutic efficacy compared to iv-infused MSCs alone. CLI was induced by external iliac arterial cauterization in 10–12-month-old mice. pFUS/MSC treatments were delayed 14 days, when surgical inflammation subsided. Mice were treated with iv-saline, pFUS alone, IV-MSC, or pFUS and IV-MSC. Proteomic analyses revealed pFUS upregulated local chemoattractants and increased MSC tropism to CLI muscle. By 7 weeks post-treatment, pFUS + MSC significantly increased perfusion and CD31 expression, while reducing fibrosis compared to saline. pFUS or MSC alone reduced fibrosis, but did not increase perfusion or CD31. Furthermore, MSCs homing to pFUS-treated CLI muscle expressed more vascular endothelial growth factor (VEGF) and interleukin-10 (IL-10) than MSCs homing to non-pFUS-treated muscle. pFUS + MSC improved perfusion and vascular density in this clinically-relevant CLI model. The molecular effects of pFUS increased both MSC homing and MSC production of VEGF and IL-10, suggesting microenvironmental changes from pFUS also increased potency of MSCs in situ to further enhance their efficacy.

Published
2017
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9. Disrupting the blood-brain barrier by focused ultrasound induces sterile inflammation

Author

Saejeong Kim, Farhan Qureshi, Scott R. Burks, Blerta Milo, Neekita Jikaria, Zsofia I. Kovacs, Joseph A. Frank, Bobbi K. Lewis, and Michele Bresler

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Ischemia, Inflammation, Blood–brain barrier, Proinflammatory cytokine, Rats, Sprague-Dawley, 03 medical and health sciences, Sonication, 0302 clinical medicine, Drug Delivery Systems, Parenchyma, medicine, Animals, HSP70 Heat-Shock Proteins, Parenchymal Tissue, Ultrasonography, Multidisciplinary, Microglia, business.industry, Tumor Necrosis Factor-alpha, Macrophages, Gene Transfer Techniques, Interleukin-18, Brain, Neurodegenerative Diseases, medicine.disease, Rats, 030104 developmental biology, medicine.anatomical_structure, Blood-Brain Barrier, Astrocytes, Interleukin 18, Tumor necrosis factor alpha, Female, medicine.symptom, business, Cell Adhesion Molecules, 030217 neurology & neurosurgery, Interleukin-1
Abstract

MRI-guided pulsed focused ultrasound (pFUS) combined with systemic infusion of ultrasound contrast agent microbubbles (MB) causes localized blood-brain barrier (BBB) disruption that is currently being advocated for increasing drug or gene delivery in neurological diseases. The mechanical acoustic cavitation effects of opening the BBB by low-intensity pFUS+MB, as evidenced by contrast-enhanced MRI, resulted in an immediate damage-associated molecular pattern (DAMP) response including elevations in heat-shock protein 70, IL-1, IL-18, and TNFα indicative of a sterile inflammatory response (SIR) in the parenchyma. Concurrent with DAMP presentation, significant elevations in proinflammatory, antiinflammatory, and trophic factors along with neurotrophic and neurogenesis factors were detected; these elevations lasted 24 h. Transcriptomic analysis of sonicated brain supported the proteomic findings and indicated that the SIR was facilitated through the induction of the NFκB pathway. Histological evaluation demonstrated increased albumin in the parenchyma that cleared by 24 h along with TUNEL+ neurons, activated astrocytes, microglia, and increased cell adhesion molecules in the vasculature. Infusion of fluorescent beads 3 d before pFUS+MB revealed the infiltration of CD68+ macrophages at 6 d postsonication, as is consistent with an innate immune response. pFUS+MB is being considered as part of a noninvasive adjuvant treatment for malignancy or neurodegenerative diseases. These results demonstrate that pFUS+MB induces an SIR compatible with ischemia or mild traumatic brain injury. Further investigation will be required before this approach can be widely implemented in clinical trials.

Published
2016

10. 5th International Symposium on Focused Ultrasound

Author

Menashe Zaaroor, Alon Sinai, Dorit Goldsher, Ayelet Eran, Maria Nassar, Ilana Schlesinger, Jonathon Parker, Vinod Ravikumar, Pejman Ghanouni, Sherman Stein, Casey Halpern, Vibhor Krishna, Amelia Hargrove, Punit Agrawal, Barbara Changizi, Eric Bourekas, Michael Knopp, Ali Rezai, Brian Mead, Namho Kim, Panagiotis Mastorakos, Jung Soo Suk, Wilson Miller, Alexander Klibanov, Justin Hanes, Richard Price, Shutao Wang, Oluyemi Olumolade, Tara Kugelman, Vernice Jackson-Lewis, Maria Eleni Karakatsani, Yang Han, Serge Przedborski, Elisa Konofagou, Kullervo Hynynen, Isabelle Aubert, Gerhard Leinenga, Rebecca Nisbet, Robert Hatch, Anneke Van der Jeugd, Harrison Evans, Jürgen Götz, Ann Van der Jeugd, Paul Fishman, Paul Yarowsky, Victor Frenkel, Shen Wei-Bin, Ben Nguyen, Carlos Sierra Sanchez, Camilo Acosta, Cherry Chen, Shih-Ying Wu, Muna Aryal, Iason T. Papademetriou, Yong-Zhi Zhang, Chanikarn Power, Nathan McDannold, Tyrone Porter, Zsofia Kovacs, Saejeong Kim, Neekita Jikaria, Farhan Qureshi, Michele Bresler, Joseph Frank, Henrik Odéen, George Chiou, John Snell, Nick Todd, Bruno Madore, Dennis Parker, Kim Butts Pauly, Mike Marx, Sumeeth Jonathan, William Grissom, Costas Arvanitis, Gregory Clement, Joshua de Bever, Allison Payne, Douglas Christensen, Guillaume Maimbourg, Mathieu David Santin, Alexandre Houdouin, Stéphane Lehericy, Mickael Tanter, Jean Francois Aubry, Christian Federau, Beat Werner, Dong-Guk Paeng, Zhiyuan Xu, Anders Quigg, Matt Eames, Changzhu Jin, Ashli Everstine, Jason Sheehan, M. Beatriz Lopes, Neal Kassell, James Drake, Karl Price, Lior Lustgarten, Vivian Sin, Charles Mougenot, Elizabeth Donner, Emily Tam, Mojgan Hodaie, Adam Waspe, Thomas Looi, Samuel Pichardo, Wonhye Lee, Yong An Chung, Yujin Jung, In-Uk Song, Seung-Schik Yoo, Hyun-Chul Kim, Jong-Hwan Lee, Charles Caskey, Wolf Zinke, Josh Cosman, Jillian Shuman, Jeffrey Schall, Christian Aurup, Hong Chen, Hermes Kamimura, Antonio Carneiro, Tao Sun, Navid Nazai, Sam Patz, Margaret Livingstone, Todd Mainprize, Yuexi Huang, Ryan Alkins, Martin Chapman, James Perry, Nir Lipsman, Allison Bethune, Arjun Sahgal, Maureen Trudeau, Hao-Li Liu, Po-Hung Hsu, Kuo-Chen Wei, Jonathan Sutton, Phillip Alexander, Eric Miller, Thiele Kobus, Alexandre Carpentier, Michael Canney, Alexandre Vignot, Kevin Beccaria, Delphine Leclercq, Cyril Lafon, Jean Yves Chapelon, Khe Hoang-Xuan, Jean-Yves Delattre, Ahmed Idbaih, David Moore, Alexis Xu, Paul Schmitt, Jessica Foley, Jonathan Sukovich, Charles Cain, Aditya Pandey, Neeraj Chaudhary, Sandra Camelo-Piragua, Steven Allen, Jon Cannata, Dejan Teofilovic, Jim Bertolina, Timothy Hall, Zhen Xu, Julien Grondin, Vincent Ferrera, Gail ter Haar, Petros Mouratidis, Elizabeth Repasky, Kelsie Timbie, Lena Badr, Benjamin Campbell, John McMichael, Andrew Buckner, Jessica Prince, Aaron Stevens, Timothy Bullock, Karin Skalina, Chandan Guha, Franco Orsi, Guido Bonomo, Paolo Della Vigna, Giovanni Mauri, Gianluca Varano, George Schade, Yak-Nam Wang, Venu Pillarisetty, Joo Ha Hwang, Vera Khokhlova, Michael Bailey, Tatiana Khokhlova, Ilya Sinilshchikov, Petr Yuldashev, Yulia Andriyakhina, Wayne Kreider, Adam Maxwell, Oleg Sapozhnikov, Ari Partanen, Jonathan Lundt, Tobias Preusser, Sabrina Haase, Mario Bezzi, Jürgen Jenne, Thomas Langø, Massimo Midiri, Michael Mueller, Giora Sat, Christine Tanner, Stephan Zangos, Matthias Guenther, Andreas Melzer, Arianna Menciassi, Selene Tognarelli, Andrea Cafarelli, Alessandro Diodato, Gastone Ciuti, Sven Rothluebbers, Julia Schwaab, Jan Strehlow, Senay Mihcin, Steffen Tretbar, Thomas Payen, Carmine Palermo, Steve Sastra, Kenneth Olive, Matthew Adams, Vasant Salgaonkar, Serena Scott, Graham Sommer, Chris Diederich, Joan Vidal-Jove, Eloi Perich, Antonio Ruiz, Manuela Velat, David Melodelima, Aurelien Dupre, Jeremy Vincenot, Chen Yao, David Perol, Michel Rivoire, Samantha Tucci, Lisa Mahakian, Brett Fite, Elizabeth Ingham, Sarah Tam, Chang-il Hwang, David Tuveson, Katherine Ferrara, Stephen Scionti, Lili Chen, Dusica Cvetkovic, Xiaoming Chen, Roohi Gupta, Bin Wang, Charlie Ma, Kenneth Bader, Kevin Haworth, Christy Holland, Narendra Sanghvi, Roy Carlson, Wohsing Chen, Christian Chaussy, Stefan Thueroff, Claudio Cesana, Carlo Bellorofonte, Qingguo Wang, Han Wang, Shengping Wang, Junhai Zhang, Alberto Bazzocchi, Alessandro Napoli, Robert Staruch, Chenchen Bing, Sumbul Shaikh, Joris Nofiele, Debra Szczepanski, Michelle Wodzak Staruch, Noelle Williams, Theodore Laetsch, Rajiv Chopra, Jarrett Rosenberg, Rachelle Bitton, Suzanne LeBlang, Joshua Meyer, Mark Hurwitz, Pavel Yarmolenko, Haydar Celik, Avinash Eranki, Viktoriya Beskin, Domiciano Santos, Janish Patel, Matthew Oetgen, AeRang Kim, Peter Kim, Karun Sharma, Alexander Chisholm, Dionne Aleman, Roberto Scipione, Michael Temple, Joao Guilherme Amaral, Ruby Endre, Maria Lamberti-Pasculli, Joost de Ruiter, Fiona Campbell, Jennifer Stimec, Samit Gupta, Manoj Singh, Sevan Hopyan, Gregory Czarnota, David Brenin, Carrie Rochman, Roussanka Kovatcheva, Jordan Vlahov, Katja Zaletel, Julian Stoinov, Matthew Bucknor, Viola Rieke, Jenny Shim, Korgun Koral, Brian Lang, Carlos Wong, Heather Lam, Alexander Shinkov, Jim Hu, Xi Zhang, Jonathan Macoskey, Kimberly Ives, Gabe Owens, Hitinder Gurm, Jiaqi Shi, Matthew Pizzuto, Christopher Dillon, Ivy Christofferson, Elaine Hilas, Jill Shea, Paul Greillier, Bénédicte Ankou, Francis Bessière, Ali Zorgani, Mathieu Pioche, Wojciech Kwiecinski, Julie Magat, Sandrine Melot-Dusseau, Romain Lacoste, Bruno Quesson, Mathieu Pernot, Stefan Catheline, Philippe Chevalier, Fabrice Marquet, Pierre Bour, Fanny Vaillant, Sana Amraoui, Rémi Dubois, Philippe Ritter, Michel Haïssaguerre, Mélèze Hocini, Olivier Bernus, Pamela Tebebi, Scott Burks, Blerta Milo, Michael Gertner, Jimin Zhang, Andrew Wong, Yu Liu, Azadeh Kheirolomoom, Jai Seo, Katherine Watson, Hua Zhang, Josquin Foiret, Alexander Borowsky, Doudou Xu, Maya Thanou, Miguell Centelles, Mike Wright, Maral Amrahli, Po-Wah So, Wladyslaw Gedroyc, Esther Kneepkens, Edwin Heijman, Jochen Keupp, Steffen Weiss, Klaas Nicolay, Holger Grüll, Matthew Nagle, Anastasia V. Nikolaeva, Marina E. Terzi, Sergey A. Tsysar, Bryan Cunitz, Pierre Mourad, Matthew Downs, Georgiana Yang, Qi Wang, Johnny Chen, Justin Farry, Adam Dixon, Zhongmin Du, Ali Dhanaliwala, John Hossack, Ashish Ranjan, Danny Maples, Rachel Wardlow, Jerry Malayer, Akhilesh Ramachandran, Hirofumi Namba, Motohiro Kawasaki, Masashi Izumi, Katsuhito Kiyasu, Ryuichi Takemasa, Masahiko Ikeuchi, Takahiro Ushida, Calum Crake, Satya V. V. N. Kothapalli, Wan Leighton, Zhaorui Wang, H. Michael Gach, William Straube, Michael Altman, Young-sun Kim, Hyo Keun Lim, Hyunchul Rhim, Johanna van Breugel, Manon Braat, Chrit Moonen, Maurice van den Bosch, Mario Ries, Cristina Marrocchio, Susan Dababou, Jae Young Lee, Hyun Hoon Chung, Soo Yeon Kang, Kook Jin Kang, Keon Ho Son, Dandan Zhang, Juan Plata, Peter Jones, Aurea Pascal-Tenorio, Donna Bouley, Aaron Bond, Robert Dallapiazza, Diane Huss, Amy Warren, Scott Sperling, Ryder Gwinn, Binit Shah, W. Jeff Elias, Colleen Curley, Ying Zhang, Karina Negron, Roger Abounader, Gesthimani Samiotaki, Tsang-Wei Tu, Georgios Papadakis, Dima Hammoud, Matthew Silvestrini, Frank Wolfram, Daniel Güllmar, Juergen Reichenbach, Denis Hofmann, Joachim Böttcher, Harald Schubert, Thomas G. Lesser, Scott Almquist, Francisco Camarena, Sergio Jiménez-Gambín, Noé Jiménez, Jin Woo Chang, Vandiver Chaplin, Rebekah Griesenauer, Michael Miga, Nicholas Ellens, Raag Airan, Alfredo Quinones-Hinojosa, Keyvan Farahani, Xue Feng, Samuel Fielden, Li Zhao, Max Wintermark, Craig Meyer, Sijia Guo, Xin Lu, Jiachen Zhuo, Su Xu, Rao Gullapalli, Dheeraj Gandhi, Omer Brokman, Hongchae Baek, Hyungmin Kim, Steven Leung, Taylor Webb, Natalia Vykhodtseva, Thai-Son Nguyen, Chang Kyu Park, Sang Man Park, Na Young Jung, Min Soo Kim, Won Seok Chang, Hyun Ho Jung, Michael Plaksin, Yoni Weissler, Shy Shoham, Eitan Kimmel, Pavel B. Rosnitskiy, Steve Krupa, Eilon Hazan, Omer Naor, Yoav Levy, Noam Maimon, Inbar Brosh, Itamar Kahn, Jessica Cahill, Elodie Constanciel Colas, Adrian Wydra, Roman Maev, Amirah Aly, Ozge Sesenoglu-Laird, Linas Padegimas, Mark Cooper, Barbara Waszczak, Seruz Tehrani, Craig Slingluff, James Larner, Kumari Andarawewa, Eugene Ozhinsky, Rutwik Shah, Roland Krug, Roel Deckers, Sabine Linn, Britt Suelmann, Arjen Witkamp, Paul Vaessen, Paul van Diest, Lambertus W. Bartels, Clemens Bos, Nicolas Borys, Gert Storm, Elsken Van der Wall, Navid Farr, Moez Alnazeer, Prateek Katti, Bradford Wood, Alexis Farrer, Cyril Ferrer, Baudouin Denis de Senneville, Marijn van Stralen, Jingfei Liu, J. Kent Leach, Stephan Zidowitz, Hsin-Lun Lee, Fang-Chi Hsu, Chia-Chun Kuo, Shiu-Chen Jeng, Tung-Ho Chen, Nai-Yi Yang, Jeng-Fong Chiou, Yi-tzu Kao, Chia-Hsin Pan, Jing-Fu Wu, Yi-Chieh Tsai, Sara Johnson, Dawei Li, Ye He, Ioannis Karakitsios, Michael Schwenke, Daniel Demedts, Xu Xiao, Ian Cavin, Emilee Minalga, Robb Merrill, Rock Hadley, Pascal Ramaekers, Martijn de Greef, Kian Shahriari, Mohammad Hossein Parvizi, Kiana Asadnia, Marzieh Chamanara, Seyed Kamran Kamrava, Hamid Reza Chabok, Ruben Stein, Sébastien Muller, Jeremy Tan, Cornel Zachiu, Hans-Peter Erasmus, Glen Van Arsdell, Lee Benson, Kee W. Jang, Mary Angstadt, Bobbi Lewis, Hailey McLean, Martijn Hoogenboom, Dylan Eikelenboom, Martijn den Brok, Pieter Wesseling, Arend Heerschap, Jurgen Fütterer, Gosse Adema, Kevin Wang, Pei Zhong, Joyce Joy, Helen McLeod, Harry Kim, Matthew Lewis, Arda Ozilgen, Peter Zahos, Dezba Coughlin, Xinyan Tang, Jeff Lotz, Kathleen Jedruszczuk, Amitabh Gulati, Stephen Solomon, Elena Kaye, John Mugler, Gaetano Barbato, Gian Luca Scoarughi, Cristiano Corso, Alessandro Gorgone, Ilaria Giuseppina Migliore, Zachary Larrabee, Arik Hananel, Jean-Francois Aubry, Ayele Negussie, Emmanuel Wilson, Reza Seifabadi, Hyungwon Moon, Jeeun Kang, Changbeom Sim, Jin Ho Chang, Hyuncheol Kim, Hak Jong Lee, Noboru Sasaki, Mitsuyoshi Takiguchi, Lukas Sebeke, Xi Luo, Bram de Jager, Maurice Heemels, Christopher Abraham, Laura Curiel, Rémi Berriet, Margit Janát-Amsbury, Joseph Corea, Patrick Peiyong Ye, Ana Clauda Arias, Micheal Lustig, and Bryant Svedin

Subjects
Pathology, medicine.medical_specialty, business.industry, Blood–brain barrier, Focused ultrasound, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, Disease therapy, 0302 clinical medicine, medicine.anatomical_structure, medicine, Radiology, Nuclear Medicine and imaging, business, 030217 neurology & neurosurgery
Published
2016
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11. APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer’s Disease Phenotypes in Human iPSC-Derived Brain Cell Types

Author

Jinsoo Seo, Jemmie Cheng, Dilip Dey, Tak Ko, Zhuyu Peng, Jay Penney, Richard Rueda, Chung Jong Yu, Hsin-Lan Wen, Blerta Milo, Hugh P. Cam, Elizabeta Gjoneska, Sara Elmsaouri, Waseem K. Raja, Li-Huei Tsai, Bruce A. Yankner, Fatema Abdurrob, Oleg Kritskiy, Heather M. Feldman, Fan Gao, Yuan-Ta Lin, Picower Institute for Learning and Memory, and Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences

Subjects
0301 basic medicine, Apolipoprotein E, Cell type, Phagocytosis, Apolipoprotein E4, Induced Pluripotent Stem Cells, Apolipoprotein E3, tau Proteins, Biology, Synaptic Transmission, Article, 03 medical and health sciences, Immune system, Alzheimer Disease, mental disorders, medicine, Humans, Secretion, Induced pluripotent stem cell, Neurons, Amyloid beta-Peptides, General Neuroscience, Brain, Cell Differentiation, Lipid metabolism, Human brain, Lipid Metabolism, Phosphoproteins, Peptide Fragments, Cell biology, Organoids, 030104 developmental biology, medicine.anatomical_structure, Astrocytes, lipids (amino acids, peptides, and proteins), Microglia, CRISPR-Cas Systems, Transcriptome, Neuroglia, human activities
Abstract

The apolipoprotein E4 (APOE4) variant is the single greatest genetic risk factor for sporadic Alzheimer's disease (sAD). However, the cell-type-specific functions of APOE4 in relation to AD pathology remain understudied. Here, we utilize CRISPR/Cas9 and induced pluripotent stem cells (iPSCs) to examine APOE4 effects on human brain cell types. Transcriptional profiling identified hundreds of differentially expressed genes in each cell type, with the most affected involving synaptic function (neurons), lipid metabolism (astrocytes), and immune response (microglia-like cells). APOE4 neurons exhibited increased synapse number and elevated Aβ42 secretion relative to isogenic APOE3 cells while APOE4 astrocytes displayed impaired Aβ uptake and cholesterol accumulation. Notably, APOE4 microglia-like cells exhibited altered morphologies, which correlated with reduced Aβ phagocytosis. Consistently, converting APOE4 to APOE3 in brain cell types from sAD iPSCs was sufficient to attenuate multiple AD-related pathologies. Our study establishes a reference for human cell-type-specific changes associated with the APOE4 variant. Video Abstract: [Figure presented] By generating and characterizing isogenic APOE3- or APOE4-carrying human brain cell types, Lin et al. show that the APOE4 variant can lead to extensive gene expression alterations, and multiple cellular phenotypes potentially related to AD pathogenesis, in neurons, astrocytes, and microglia., National Institutes of Health (NIH) (Grants RF1-AG048056, RC1-AG036106, and RF1-AG048029)

Published
2018
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12. Enhanced stem cell and progenitor cell homing following IV injection to skeletal muscle in a murine model of muscular dystrophy induced by pulsed focused ultrasound (pFUS)

Author

Blerta Milo, Scott R. Burks, Sage Kim, Ben Nguyen, Joseph A. Frank, and Michele Bresler

Subjects
Cancer Research, Transplantation, Pathology, medicine.medical_specialty, business.industry, Immunology, Skeletal muscle, Cell Biology, medicine.disease, IV injection, Focused ultrasound, medicine.anatomical_structure, Oncology, Murine model, medicine, Immunology and Allergy, Muscular dystrophy, Stem cell, Progenitor cell, business, Genetics (clinical), Homing (hematopoietic)
Published
2015
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