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3. Runx1 is sufficient but not required for cardiomyocyte cell cycle activation

Author

Akins, Kaelin A., primary, Flinn, Michael A., additional, Swift, Samantha K., additional, Chanjeevaram, Smrithi V., additional, Purdy, Alexandra L., additional, Buddell, Tyler, additional, Kolell, Mary E., additional, Andresen, Kaitlyn G., additional, Paddock, Samantha, additional, Buday, Sydney L., additional, O'Meara, Caitlin C., additional, Veldman, Matthew B., additional, and Patterson, Michaela, additional

Published
2024
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7. Frequency of mononuclear diploid cardiomyocytes underlies natural variation in heart regeneration

Author

Patterson, Michaela, Barske, Lindsey, Van Handel, Ben, Rau, Christoph D, Gan, Peiheng, Sharma, Avneesh, Parikh, Shan, Denholtz, Matt, Huang, Ying, Yamaguchi, Yukiko, Shen, Hua, Allayee, Hooman, Crump, J Gage, Force, Thomas I, Lien, Ching-Ling, Makita, Takako, Lusis, Aldons J, Kumar, S Ram, and Sucov, Henry M

Subjects
Biological Sciences, Genetics, Cardiovascular, Regenerative Medicine, Heart Disease, Animals, Animals, Genetically Modified, Cells, Cultured, Diploidy, Gene Expression Profiling, Heart, Immunoblotting, In Situ Hybridization, Fluorescence, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Microscopy, Confocal, Myocardium, Myocytes, Cardiac, Protein Kinases, Protein Serine-Threonine Kinases, Regeneration, Zebrafish, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Adult mammalian cardiomyocyte regeneration after injury is thought to be minimal. Mononuclear diploid cardiomyocytes (MNDCMs), a relatively small subpopulation in the adult heart, may account for the observed degree of regeneration, but this has not been tested. We surveyed 120 inbred mouse strains and found that the frequency of adult mononuclear cardiomyocytes was surprisingly variable (>7-fold). Cardiomyocyte proliferation and heart functional recovery after coronary artery ligation both correlated with pre-injury MNDCM content. Using genome-wide association, we identified Tnni3k as one gene that influences variation in this composition and demonstrated that Tnni3k knockout resulted in elevated MNDCM content and increased cardiomyocyte proliferation after injury. Reciprocally, overexpression of Tnni3k in zebrafish promoted cardiomyocyte polyploidization and compromised heart regeneration. Our results corroborate the relevance of MNDCMs in heart regeneration. Moreover, they imply that intrinsic heart regeneration is not limited nor uniform in all individuals, but rather is a variable trait influenced by multiple genes.

Published
2017

8. IL-13 promotes functional recovery after myocardial infarction via direct signaling to macrophages

Author

Alvarez-Argote, Santiago, primary, Paddock, Samantha J., additional, Flinn, Michael A., additional, Moreno, Caelan W., additional, Knas, Makenna C., additional, Almeida, Victor A., additional, Buday, Sydney L., additional, Bakhshian Nik, Amirala, additional, Patterson, Michaela, additional, Chen, Yi-Guang, additional, Lin, Chien-Wei, additional, and O’Meara, Caitlin C., additional

Published
2024
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10. Dynamic distribution of linker histone H1.5 in cellular differentiation.

Author

Li, Jing-Yu, Patterson, Michaela, Mikkola, Hanna KA, Lowry, William E, and Kurdistani, Siavash K

Subjects
Germ Cells, Chromatin, Heterochromatin, Fibroblasts, Humans, DNA-Binding Proteins, Membrane Proteins, Histones, Cell Differentiation, Gene Expression Regulation, Developmental, Embryonic Stem Cells, Jumonji Domain-Containing Histone Demethylases, Sirtuin 1, Gene Expression Regulation, Developmental, Genetics, Developmental Biology
Abstract

Linker histones are essential components of chromatin, but the distributions and functions of many during cellular differentiation are not well understood. Here, we show that H1.5 binds to genic and intergenic regions, forming blocks of enrichment, in differentiated human cells from all three embryonic germ layers but not in embryonic stem cells. In differentiated cells, H1.5, but not H1.3, binds preferentially to genes that encode membrane and membrane-related proteins. Strikingly, 37% of H1.5 target genes belong to gene family clusters, groups of homologous genes that are located in proximity to each other on chromosomes. H1.5 binding is associated with gene repression and is required for SIRT1 binding, H3K9me2 enrichment, and chromatin compaction. Depletion of H1.5 results in loss of SIRT1 and H3K9me2, increased chromatin accessibility, deregulation of gene expression, and decreased cell growth. Our data reveal for the first time a specific and novel function for linker histone subtype H1.5 in maintenance of condensed chromatin at defined gene families in differentiated human cells.

Published
2012

14. Myofibroblast Ccn3 is regulated by Yap and Wwtr1 and contributes to adverse cardiac outcomes

Author

Flinn, Michael A., primary, Alvarez-Argote, Santiago, additional, Knas, Makenna C., additional, Almeida, Victor Alencar, additional, Paddock, Samantha J., additional, Zhou, Xiaoxu, additional, Buddell, Tyler, additional, Jamal, Ayana, additional, Taylor, Reiauna, additional, Liu, Pengyuan, additional, Drnevich, Jenny, additional, Patterson, Michaela, additional, Link, Brian A., additional, and O’Meara, Caitlin C., additional

Published
2023
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16. Myofibroblast Ccn3 is regulated by Yap and Wwtr1 and contributes to adverse cardiac outcomes

Author

Flinn, Michael A., primary, Alvarez-Argote, Santiago, additional, Knas, Makenna C., additional, Almeida, Victor Alencar, additional, Paddock, Samantha J., additional, Zhou, Xiaoxu, additional, Buddell, Tyler, additional, Jamal, Ayana, additional, Liu, Pengyuan, additional, Drnevich, Jenny, additional, Patterson, Michaela, additional, Link, Brian A., additional, and O’Meara, Caitlin C., additional

Published
2022
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18. Abstract P2049: Myofibroblast Depletion Of Yap And Wwtr1 Improves Cardiac Function After Myocardial Infarction Via Ccn3 Suppression

Author

Flinn, Michael A, primary, Alvarez, Santiago, additional, Knas, Makenna C, additional, Alencar, Victor, additional, Paddock, Samantha, additional, Zhou, Xiaoxu, additional, Buddell, Tyler, additional, Jamal, Ayana, additional, Liu, Pengyuan, additional, Drnevich, Jenny, additional, Patterson, Michaela, additional, Link, Brian, additional, and Omeara, Caitlin, additional

Published
2022
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25. Protocol for quantifying murine cardiomyocyte cell division by single-cell suspension

Author

Swift, Samantha K., Purdy, Alexandra L., and Patterson, Michaela

Abstract

The cardiac regeneration and development fields lack low-barrier-to-entry techniques that distinguish cardiomyocyte division from alternative outcomes in vivo. Here, we present a protocol in rodents to determine if cardiomyocyte cell division has occurred. We describe thymidine analog administration, Langendorff procedure, immunofluorescent labeling, microscopy, and analysis of fluorescent images to assess ploidy, thereby allowing an investigator to retrospectively claim cell division. Finally, we provide instructions for additional metrics including quantification of total cardiomyocytes, total cycling cardiomyocytes, and cellular dimensions.

Published
2024
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26. Reducing amyloid plaque burden via ex vivo gene delivery of an A[beta]-degrading protease: a novel therapeutic approach to Alzheimer disease

Author

Hemming, Matthew L., Patterson, Michaela, Reske-Nielsen, Casper, Lin, Ling, Isacson, Ole, and Selkoe, Dennis J.

Subjects
Alzheimer's disease -- Drug therapy, Amyloid beta-protein -- Influence, Proteases -- Research, Diseases -- Causes and theories of causation
Abstract

Background Understanding the mechanisms of amyloid-[beta] protein (A[beta]) production and clearance in the brain has been essential to elucidating the etiology of Alzheimer disease (AD). Chronically decreasing brain A[beta] levels [...]

Published
2007

27. Modeling Human Neural Development Using Pluripotent Stem Cells

Author

Patterson, Michaela Cyr

Subjects
Developmental biology, human development, human fetal tissue, let-7, LIN28, pluripotent stem cell
Abstract

Human pluripotent stem cells (hPSCs) are derived from the developing blastocyst or through transcription factor based reprogramming. hPSCs have the capacity to self-renew and give rise to all cell types of the human body. These two defining characteristics make them attractive for a variety of uses including regenerative medicine and modeling human development and disease. While it is clear that hPSCs can differentiate into all cell types, it is unknown how similar hPSC derivatives are to cells that have undergone development in vivo. Using previously established differentiation protocols we demonstrated that both types of hPSCs could generate functional motor neurons that displayed repetitive action potentials characteristic of mature motor neurons. Furthermore, these motor neurons differentiated through a progressive and predictable induction of developmental stages, suggesting hPSC differentiation appears to obey normal developmental progression. In a comprehensive comparison of hPSC derivatives and tissue-derived counterparts, we determined that the progeny of hPSCs are most similar to a cell type found prior to 6 weeks of gestation. These hPSC derivatives continued to express genes normally found at 3-5 weeks of gestation, including LIN28; while tissue derived counterparts had already silenced these genes. In vitro function demonstrated that hPSC derivatives also acted like developmentally primitive cells. These findings suggest that developmental timing is conserved in vitro and perhaps even innate to the differentiating cell. Finally, we explored the role of the LIN28/let-7 pathway on the developmental maturity of hPSC-derived neural progenitor cells (hPSC-NPCs) as measured by their ability to generate neurons or glia. We determined that addition of let-7s into hPSC-NPCs can correct a significant number of the genes differentially expressed between hPSC derivatives and tissue-derived counterparts. Furthermore, the manipulation has a modest, but significant effect on the functional maturity of PSC-NPCs. Taken together, these data demonstrate that hPSCs can serve as an excellent and tractable model of human development.

Published
2012

35. A broadly applicable method for quantifying cardiomyocyte cell division identifies proliferative events following myocardial infarction

Author

Swift, Samantha K., Purdy, Alexandra L., Buddell, Tyler, Lovett, Jerrell J., Chanjeevaram, Smrithi V., Arkatkar, Anooj, O’Meara, Caitlin C., and Patterson, Michaela

Abstract

Cardiomyocyte proliferation is a challenging metric to assess. Current methodologies have limitations in detecting the generation of new cardiomyocytes and technical challenges that reduce widespread applicability. Here, we describe an improved cell suspension and imaging-based methodology that can be broadly employed to assess cardiomyocyte cell division in standard laboratories across a multitude of model organisms and experimental conditions. We highlight additional metrics that can be gathered from the same cell preparations to enable additional relevant analyses to be performed. We incorporate additional antibody stains to address potential technical concerns of miscounting. Finally, we employ this methodology with a dual-thymidine analog-labeling approach to a post-infarction murine model, which allowed us to robustly identify unique cycling events, such as cardiomyocytes undergoing multiple rounds of cell division.

Published
2024
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40. Addressing Culturally Based Hidden Bias and RacisM (A-CHARM) Using Simulation Experiences, Nik’s Story: A Quasi-Experimental Study

Author

Sawhney, Monakshi, Li, Jenny S., Patterson, Michaela, Gumapac, Nathaniel P., Sau, Crystal, and Akbari, Ali

Abstract

Background/Purpose Racism and hidden bias experienced by underrepresented nursing students contribute to a loss of confidence and anxiety. The A-CHARM nursing project developed virtual simulation experiences for nursing students to practice how to address racism. ‘Nik's Story’ virtual simulation was created as part of the A-CHARM project. The purpose of this study was to examine the effectiveness of an education intervention, that included Nik's story, on cultural humility and cultural diversity awareness.Method This quasi-experimental study included a convenience sample of final year nursing students. After informed consent, participants completed a pre-intervention questionnaire that included the Cultural Humility Scale “context for difference in perspective” subscale, and the Cultural Diversity Awareness questionnaire to assess baseline knowledge. Students participated in an education intervention that included a lecture, Nik's story virtual simulation experience, a debrief and then completed a post-education/simulation questionnaire that included usability/learner engagement questions and the Cultural Humility Scale “context for difference in perspective” subscale, and the Cultural Diversity Awareness questionnaire.Results Forty-seven students consented and completed the pre/post intervention questionnaire. Participants rated the effectiveness, engagement and usability of the simulation experience highly. There was a significant positive change in cultural humility “context for difference in perspective” subscale (pre-scores = 6.9, SD = 3.3; post-scores = 31.0, SD = 3.8, p< 0.001), and cultural diversity awareness (pre-scores = 95.4, SD = 8.9; post-scores = 103.4, SD = 9.8, p< 0.001).Discussion This intervention was effective in improving cultural humility and cultural diversity awareness in nursing students.Conclusion Simulation experiences regarding racism in the clinical setting provide a strategy for students to learn how to professionally navigate unwanted experiences.

Published
2024
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42. Nipah Virus Envelope-Pseudotyped Lentiviruses Efficiently Target ephrinB2-Positive Stem Cell Populations In Vitro and Bypass the Liver Sink When Administered In Vivo

Author

Palomares, Karina, primary, Vigant, Frederic, additional, Van Handel, Ben, additional, Pernet, Olivier, additional, Chikere, Kelechi, additional, Hong, Patrick, additional, Sherman, Sean P., additional, Patterson, Michaela, additional, An, Dong Sung, additional, Lowry, William E., additional, Mikkola, Hanna K. A., additional, Morizono, Kouki, additional, Pyle, April D., additional, and Lee, Benhur, additional

Published
2013
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43. From Skin Biopsy to Neurons Through a Pluripotent Intermediate Under Good Manufacturing Practice Protocols

Author

Karumbayaram, Saravanan, primary, Lee, Peiyee, additional, Azghadi, Soheila F., additional, Cooper, Aaron R., additional, Patterson, Michaela, additional, Kohn, Donald B., additional, Pyle, April, additional, Clark, Amander, additional, Byrne, James, additional, Zack, Jerome A., additional, Plath, Kathrin, additional, and Lowry, William E., additional

Published
2011
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46. Female Human iPSCs Retain an Inactive X Chromosome

Author

Tchieu, Jason, primary, Kuoy, Edward, additional, Chin, Mark H., additional, Trinh, Hung, additional, Patterson, Michaela, additional, Sherman, Sean P., additional, Aimiuwu, Otaren, additional, Lindgren, Anne, additional, Hakimian, Shahrad, additional, Zack, Jerome A., additional, Clark, Amander T., additional, Pyle, April D., additional, Lowry, William E., additional, and Plath, Kathrin, additional

Published
2010
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47. Directed Differentiation of Human-Induced Pluripotent Stem Cells Generates Active Motor Neurons

Author

Karumbayaram, Saravanan, primary, Novitch, Bennett G., additional, Patterson, Michaela, additional, Umbach, Joy A., additional, Richter, Laura, additional, Lindgren, Anne, additional, Conway, Anne E., additional, Clark, Amander T., additional, Goldman, Steve A., additional, Plath, Kathrin, additional, Wiedau-pazos, Martina, additional, Kornblum, Harley I., additional, and Lowry, William E., additional

Published
2009
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48. Dynamic Distribution of Linker Histone H1.5 in Cellular Differentiation.

Author

Jing-Yu Li, Patterson, Michaela, Mikkola, Hanna K. A., Lowry, William E., and Kurdistani, Siavash K.

Subjects
*HISTONE genetics, *MOLECULAR structure of chromatin, *HUMAN cell culture, *CELL differentiation, *CELL growth
Abstract

Linker histones are essential components of chromatin, but the distributions and functions of many during cellular differentiation are not well understood. Here, we show that H1.5 binds to genic and intergenic regions, forming blocks of enrichment, in differentiated human cells from all three embryonic germ layers but not in embryonic stem cells. In differentiated cells, H1.5, but not H1.3, binds preferentially to genes that encode membrane and membrane-related proteins. Strikingly, 37% of H1.5 target genes belong to gene family clusters, groups of homologous genes that are located in proximity to each other on chromosomes. H1.5 binding is associated with gene repression and is required for SIRT1 binding, H3K9me2 enrichment, and chromatin compaction. Depletion of H1.5 results in loss of SIRT1 and H3K9me2, increased chromatin accessibility, deregulation of gene expression, and decreased cell growth. Our data reveal for the first time a specific and novel function for linker histone subtype H1.5 in maintenance of condensed chromatin at defined gene families in differentiated human cells. [ABSTRACT FROM AUTHOR]

Published
2012
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49. Defining the nature of human pluripotent stem cell progeny.

Author

Patterson, Michaela, Chan, David N., Ha, Iris, Case, Dana, Cui, Yongyan, Handel, Ben Van, Mikkola, Hanna KA, and Lowry, William E

Subjects
PLURIPOTENT stem cells, TISSUES, MESENCHYMAL stem cells, FETAL tissues, GENES
Abstract

While it is clear that human pluripotent stem cells (hPSCs) can differentiate to generate a panoply of various cell types, it is unknown how closely in vitro development mirrors that which occurs in vivo. To determine whether human embryonic stem cells (hESCs) and human-induced pluripotent stem cells (hiPSCs) make equivalent progeny, and whether either makes cells that are analogous to tissue-derived cells, we performed comprehensive transcriptome profiling of purified PSC derivatives and their tissue-derived counterparts. Expression profiling demonstrated that hESCs and hiPSCs make nearly identical progeny for the neural, hepatic, and mesenchymal lineages, and an absence of re-expression from exogenous reprogramming factors in hiPSC progeny. However, when compared to a tissue-derived counterpart, the progeny of both hESCs and hiPSCs maintained expression of a subset of genes normally associated with early mammalian development, regardless of the type of cell generated. While pluripotent genes (OCT4, SOX2, REX1, and NANOG) appeared to be silenced immediately upon differentiation from hPSCs, genes normally unique to early embryos (LIN28A, LIN28B, DPPA4, and others) were not fully silenced in hPSC derivatives. These data and evidence from expression patterns in early human fetal tissue (3-16 weeks of development) suggest that the differentiated progeny of hPSCs are reflective of very early human development (< 6 weeks). These findings provide support for the idea that hPSCs can serve as useful in vitro models of early human development, but also raise important issues for disease modeling and the clinical application of hPSC derivatives. [ABSTRACT FROM AUTHOR]

Published
2012
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50. Reducing Amyloid Plaque Burden via Ex Vivo Gene Delivery of an Aβ-Degrading Protease: A Novel Therapeutic Approach to Alzheimer Disease

Author

Patterson, Michaela, Reske-Nielsen, Casper, Hemming, Matthew Louis, Lin, Ling, Isacson, Ole Stefan, and Selkoe, Dennis J.

Subjects
biochemistry, neurological disorders, neuroscience, pathology, neurology, dementia
Abstract

Background: Understanding the mechanisms of amyloid-β protein (Aβ) production and clearance in the brain has been essential to elucidating the etiology of Alzheimer disease (AD). Chronically decreasing brain Aβ levels is an emerging therapeutic approach for AD, but no such disease-modifying agents have achieved clinical validation. Certain proteases are responsible for the catabolism of brain Aβ in vivo, and some experimental evidence suggests they could be used as therapeutic tools to reduce Aβ levels in AD. The objective of this study was to determine if enhancing the clearance of Aβ in the brain by ex vivo gene delivery of an Aβ-degrading protease can reduce amyloid plaque burden. Methods and Findings: We generated a secreted form of the Aβ-degrading protease neprilysin, which significantly lowers the levels of naturally secreted Aβ in cell culture. We then used an ex vivo gene delivery approach utilizing primary fibroblasts to introduce this soluble protease into the brains of β-amyloid precursor protein (APP) transgenic mice with advanced plaque deposition. Brain examination after cell implantation revealed robust clearance of plaques at the site of engraftment (72% reduction, p = 0.0269), as well as significant reductions in plaque burden in both the medial and lateral hippocampus distal to the implantation site (34% reduction, p = 0.0020; and 55% reduction, p = 0.0081, respectively). Conclusions: Ex vivo gene delivery of an Aβ-degrading protease reduces amyloid plaque burden in transgenic mice expressing human APP. These results support the use of Aβ-degrading proteases as a means to therapeutically lower Aβ levels and encourage further exploration of ex vivo gene delivery for the treatment of Alzheimer disease.

Published
2007
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