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1. Expansion on stromal cells preserves the undifferentiated state of human hematopoietic stem cells despite compromised reconstitution ability.

Author

Mattias Magnusson, Maria I Sierra, Rajkumar Sasidharan, Sacha L Prashad, Melissa Romero, Pamela Saarikoski, Ben Van Handel, Andy Huang, Xinmin Li, and Hanna K A Mikkola

Subjects
Medicine, Science
Abstract

Lack of HLA-matched hematopoietic stem cells (HSC) limits the number of patients with life-threatening blood disorders that can be treated by HSC transplantation. So far, insufficient understanding of the regulatory mechanisms governing human HSC has precluded the development of effective protocols for culturing HSC for therapeutic use and molecular studies. We defined a culture system using OP9M2 mesenchymal stem cell (MSC) stroma that protects human hematopoietic stem/progenitor cells (HSPC) from differentiation and apoptosis. In addition, it facilitates a dramatic expansion of multipotent progenitors that retain the immunophenotype (CD34+CD38-CD90+) characteristic of human HSPC and proliferative potential over several weeks in culture. In contrast, transplantable HSC could be maintained, but not significantly expanded, during 2-week culture. Temporal analysis of the transcriptome of the ex vivo expanded CD34+CD38-CD90+ cells documented remarkable stability of most transcriptional regulators known to govern the undifferentiated HSC state. Nevertheless, it revealed dynamic fluctuations in transcriptional programs that associate with HSC behavior and may compromise HSC function, such as dysregulation of PBX1 regulated genetic networks. This culture system serves now as a platform for modeling human multilineage hematopoietic stem/progenitor cell hierarchy and studying the complex regulation of HSC identity and function required for successful ex vivo expansion of transplantable HSC.

Published
2013
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2. Discovery-based science education: functional genomic dissection in Drosophila by undergraduate researchers.

Author

Jiong Chen, Gerald B Call, Elsa Beyer, Chris Bui, Albert Cespedes, Amy Chan, Jenny Chan, Stacy Chan, Akanksha Chhabra, Peter Dang, Artemis Deravanesian, Brenda Hermogeno, James Jen, Eunha Kim, Eric Lee, Gemma Lewis, Jamie Marshall, Kirsten Regalia, Farnaz Shadpour, Aram Shemmassian, Kristin Spivey, Maggie Wells, Joy Wu, Yuki Yamauchi, Amir Yavari, Anna Abrams, Amanda Abramson, Latiffe Amado, Jenny Anderson, Keenan Bashour, Elena Bibikova, Allen Bookatz, Sarah Brewer, Natalie Buu, Stephanie Calvillo, Joseph Cao, Aileen Chang, Daniel Chang, Yuli Chang, Yibing Chen, Joo Choi, Jeyling Chou, Sumit Datta, Ardy Davarifar, Poonam Desai, Jordan Fabrikant, Shahbaz Farnad, Katherine Fu, Eddie Garcia, Nick Garrone, Srpouhi Gasparyan, Phyllis Gayda, Chad Goffstein, Courtney Gonzalez, Mariam Guirguis, Ryan Hassid, Aria Hong, Julie Hong, Lindsay Hovestreydt, Charles Hu, Farid Jamshidian, Katrin Kahen, Linda Kao, Melissa Kelley, Thomas Kho, Sarah Kim, Yein Kim, Brian Kirkpatrick, Emil Kohan, Robert Kwak, Adam Langenbacher, Santino Laxamana, Chris Lee, Janet Lee, So-Youn Lee, To Hang S Lee, Toni Lee, Sheila Lezcano, Henry Lin, Peter Lin, Julie Luu, Thanh Luu, Will Marrs, Erin Marsh, Sarah Min, Tanya Minasian, Amit Misra, Miles Morimoto, Yasaman Moshfegh, Jessica Murray, Cynthia Nguyen, Kha Nguyen, Ernesto Nodado, Amanda O'Donahue, Ndidi Onugha, Nneka Orjiakor, Bhavin Padhiar, Mara Pavel-Dinu, Alex Pavlenko, Edwin Paz, Sarah Phaklides, Lephong Pham, Preethi Poulose, Russell Powell, Aya Pusic, Divi Ramola, Meghann Ribbens, Bassel Rifai, Desiree Rosselli, Manyak Saakyan, Pamela Saarikoski, Miriam Segura, Ramnik Singh, Vivek Singh, Emily Skinner, Daniel Solomin, Kosha Soneji, Erika Stageberg, Marina Stavchanskiy, Leena Tekchandani, Leo Thai, Jayantha Thiyanaratnam, Maurine Tong, Aneet Toor, Steve Tovar, Kelly Trangsrud, Wah-Yung Tsang, Marc Uemura, Mary Unkovic, Emily Vollmer, Emily Weiss, Damien Wood, Sophia Wu, Winston Wu, Qing Xu, Kevin Yackle, Will Yarosh, Laura Yee, George Yen, Grant Alkin, Sheryllene Go, Devon M Huff, Helena Minye, Eric Paul, Nikki Villarasa, Allison Milchanowski, and Utpal Banerjee

Subjects
Biology (General), QH301-705.5
Published
2005
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4. Medial HOXA genes demarcate haematopoietic stem cell fate during human development

Author

Diana R. Dou, Vincenzo Calvanese, Maria I. Sierra, Andrew T. Nguyen, Arazin Minasian, Pamela Saarikoski, Rajkumar Sasidharan, Christina M. Ramirez, Jerome A. Zack, Gay M. Crooks, Zoran Galic, and Hanna K. A. Mikkola

Subjects
0301 basic medicine, Cellular differentiation, Cells, 1.1 Normal biological development and functioning, Antigens, CD34, Biology, Regenerative Medicine, Medical and Health Sciences, Article, 03 medical and health sciences, Underpinning research, Stem Cell Research - Nonembryonic - Human, Genetics, Humans, Homeobox, Cell Lineage, Progenitor cell, Antigens, Stem Cell Research - Embryonic - Human, Induced pluripotent stem cell, Cells, Cultured, Homeodomain Proteins, Transplantation, Cultured, Multipotent Stem Cells, Gene Expression Profiling, Genes, Homeobox, Cell Differentiation, Cell Biology, Biological Sciences, Hematopoietic Stem Cells, Stem Cell Research, Embryonic stem cell, Cell biology, Haematopoiesis, 030104 developmental biology, Genes, Multipotent Stem Cell, Leukocyte Common Antigens, CD34, Stem cell, Transcriptome, Adult stem cell, Developmental Biology
Abstract

Pluripotent stem cells (PSCs) may provide a potential source of haematopoietic stem/progenitor cells (HSPCs) for transplantation; however, unknown molecular barriers prevent the self-renewal of PSC-HSPCs. Using two-step differentiation, human embryonic stem cells (hESCs) differentiated in vitro into multipotent haematopoietic cells that had the CD34(+)CD38(-/lo)CD90(+)CD45(+)GPI-80(+) fetal liver (FL) HSPC immunophenotype, but exhibited poor expansion potential and engraftment ability. Transcriptome analysis of immunophenotypic hESC-HSPCs revealed that, despite their molecular resemblance to FL-HSPCs, medial HOXA genes remained suppressed. Knockdown of HOXA7 disrupted FL-HSPC function and caused transcriptome dysregulation that resembled hESC-derived progenitors. Overexpression of medial HOXA genes prolonged FL-HSPC maintenance but was insufficient to confer self-renewal to hESC-HSPCs. Stimulation of retinoic acid signalling during endothelial-to-haematopoietic transition induced the HOXA cluster and other HSC/definitive haemogenic endothelium genes, and prolonged HSPC maintenance in culture. Thus, medial HOXA gene expression induced by retinoic acid signalling marks the establishment of the definitive HSPC fate and controls HSPC identity and function.

Published
2016

5. Genomewide Clonal Analysis of Lethal Mutations in the Drosophila melanogaster Eye: Comparison of the X Chromosome and Autosomes

Author

Christopher Lee, Thanh Luu, Maurine Tong, Cheryl Chan, Thomas Walsh, Mabel Chin, Jiong Chen, Jacob Makshanoff, Diane Vo, Yuli Chang, John M. Olson, Tony Hung, Yuki Yamauchi, Manyak Saakyan, Renata P. Lerner, Elizabeth Evers, Latiffe Amado, Nick Garrone, Carol Salame, Jesse M. Zaretsky, Eric Paul, Winston Wu, Trinh Tran, David Kohanchi, James Z. Hui, Neetika Srivastava, Allison M. Yabroff, Aria Hong, Daniel Solomin, Preethi Poulose, Brian Kirkpatrick, Katherine Wu, Eunha Kim, Abbas Anwar, Diane Tan, Nneka Orjiakor, Utpal Banerjee, Lindsay Hovestreydt, Riju Gupta, Michael Hsieh, Jian-ya Lin, Jennifer Leighn. Sta.Ana, Alex Pavlenko, Ardy Davarifar, Stephanie S. Latterman, Shekhar S. Pai, Qing Xu, Phyllis Gayda, Amir Yavari, Allen Bookatz, Kathy T. Ngo, Paul D. Picard, Srpouhi Gasparyan, ToHang S. Lee, Emily Skinner, Sanjit Datta, Jennifer D. Trinh, Sarah Brewer, Courtney Gonzalez, Matteo Pellegrini, Desiree Rosselli, Gerald B. Call, Gemma Lewis, Kosha Soneji, Quynh-Minh Tran, Amy W. Ku, Farzin Farshidi, Cynthia Nguyen, Vivek Singh, Tanya Minasian, Mara Pavel-Dinu, Chad Goffstein, Bryon C. Lim, So-Youn Lee, Stephanie S. Lauw, Long H. Nguyen, Kevin Yackle, Will Yarosh, Santino Laxamana, Chelsea E. Taber, Sarah Kim, Tiffany Liu, Stacy Chan, Armonde Baghdanian, Kelly Trangsrud, Robert Kwak, Gelsey L. Goodstein, Farnaz Shadpour, Mariam Guirguis, Wah-Yung Tsang, Jayantha Thiyanaratnam, Edwin Paz, Chloe Knudsen-Robbins, Tatiana Moroz, Arlene J. Formanes, Mei L. Iao, Latifat Alli, Shawn S. Badal, Kathleen Lin, PhuongThao Tran, Jamie L. Marshall, Regan S. Wong, Akanksha Chhabra, Ran X. Zhu, Amanda Abramson, Sarah Min, Amit Misra, Vanessa Soma, Blake E. Haas, Eddie Garcia, Ndidi Onugha, Divi Ramola, Ya-Whey Wu, Bogdana Kovshilovskaya, Crystal P. Y. Lui, Kai C. Lei, Jeyling Chou, Yasaman Moshfegh, Sohrab Sidhu, Mark E. L. Landig, Michael G. Yeranosian, James S. Yu, Laura Yee, Lydia S-H. Kim, Katrina Fischer, Angela Y. Kim, Junia J. Song, Melissa M. Kelley, Sheila Lezcano, Jingwen Tan, Vincent Luong, Jennifer J. Zhou, Christopher N.H. Bui, Jenny Chan, Sophia D. Jin, Natalie Buu, Emily Weiss, Amanda O'Donahue, Christian Sanchez, Andrew Folick, Nkau X. V. Yang, Christie Sun, Lephong Pham, Stephanie Calvillo, Charles Hu, Yein Kim, Aileen Chang, George Yen, Joy Wu, Poonam Desai, Linda Kao, Emily G. Travis, Mary Unkovic, Damien Wood, Miriam Segura, Marc Uemura, Henry Lin, Maggie Wells, Miles Morimoto, Sumit Datta, Kha Nguyen, Jessica Wickland, Christina C. Seifert, Leo Thai, Bhavin Padhiar, Hei J. Chan, Yibing Chen, Abhishek Shah, Julie Hong, Cheng R. Huang, Sara A. Baumann, Xibin A. Cheng, Russell Powell, Shawn J. Cokus, Sonia Arevalo, Anna L. Abrams, Mark Engeln, Minh-Tu Do, Joseph Cao, JiEun Lee, Brenda Hermogeno, Bassel Rifai, Preethika S Ekanayake, Alison S. Teruya, Carlyn Crisostomo, Lesley L. Leung, Toni Lee, Megan King, Amy Chan, William R. Marrs, Ryan Hassid, Elena Bibikova, Adam D. Langenbacher, Francie Diep, Jun Gong, Joann S. Lee, Manish Pandya, Emil Kohan, Daniel S. Lee, Jenny Anderson, Kristin Spivey, Devon M Huff, Yulee Kim, Thomas Kho, Alma Rangel, Janet Lee, Aneet Toor, Pamela Saarikoski, Nikki Villarasa, Julie Luu, Vivian N. Becerra, Yara A. Mikhaeil, Shahbaz Farnad, Vida Chitsazzadeh, Q. Angela Fang, Ju An, Leena Tekchandani, Tharani Prasad, Elsa Beyer, Christopher M. Allen, Fleurette Chong, Eric Lee, Meghann Ribbens, Sherrylene Go, Amrita K. Cheema, Jordan Fabrikant, Michael Safaee, An-Chi Mei, Peter Lin, Jessica Murray, Nina Sanchez, Katherine Fu, Sacha L. Prashad, Artemis Deravanesian, Erin Marsh, Robyn Tikia, Raymond W. Kung, Sarah Phaklides, Oganes H. Shilgevorkyan, Peter Dang, Aadit R. Patel, Erika Stageberg, Helena Minye, Alexander N. Patananan, Albert Cespedes, Kasey Topp, Vicky Hahm, Keenan Bashour, Joo Choi, Daniel Chang, Majid Moarefi, William Kim, Farid Jamshidian, Inderroop Singh, Aileen E. Chang, Miguel Meza, Edward Kuoy, Danny Ayoub, Aya Pusic, Daniel Sitz, Marina Stavchanskiy, Sophia Wu, Emily Vollmer, Angela Delosreyes, James Jen, Ernesto Nodado, Aram Shemmassian, Kirsten Regalia, Ramnik Singh, Arthur H. Baghdanian, Steve Tovar, H-C. Angela Liu, and Katrin Kahen

Subjects
Genetics Education, Genetics, Mutation, Genes, Essential, X Chromosome, Autosome, Genome, Insect, Genes, Insect, Biology, Eye, biology.organism_classification, medicine.disease_cause, Clonal analysis, Clone Cells, Drosophila melanogaster, medicine, Eye development, Animals, Genes, Lethal, Drosophila (subgenus), Gene, X chromosome
Abstract

Using a large consortium of undergraduate students in an organized program at the University of California, Los Angeles (UCLA), we have undertaken a functional genomic screen in the Drosophila eye. In addition to the educational value of discovery-based learning, this article presents the first comprehensive genomewide analysis of essential genes involved in eye development. The data reveal the surprising result that the X chromosome has almost twice the frequency of essential genes involved in eye development as that found on the autosomes.

Published
2007
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6. Inability to Express HOXA Cluster and BCL11A Genes Compromises Self-Renewal and Multipotency of hESC-Derived Hematopoietic Cells

Author

Diana R Dou, Arazin Minasian, Maria I Sierra, Pamela Saarikoski, Jian Xu, Stuart H. Orkin, Sacha L. Prashad, Mattias Magnusson, Jerome A. Zack, Gay M. Crooks, Zoran Galic, and Hanna K. A. Mikkola

Subjects
Hemogenic endothelium, Developmental maturation, Immunology, Mesenchymal stem cell, Cell Biology, Hematology, Biology, Biochemistry, Embryonic stem cell, Cell biology, Haematopoiesis, CD90, Progenitor cell, Stem cell
Abstract

Abstract 1190 The inability to derive functional hematopoietic stem cells (HSCs) in vitro from pluripotent cells prevents widespread utilization of HSCs in the clinic; however, the molecular defects compromising the in vitro generated hematopoietic stem/progenitor cells (HSPCs) are unknown. Using a two-step differentiation method in which human embryonic stem cells (hESCs) were first differentiated into embryo bodies (EBs) and then CD34+ cells from hEBs were co-cultured on OP9M2 bone marrow mesenchymal stem cell (MSC) stroma (hEB-OP9), we were able to derive HSPCs expressing the HSC immunophenotype (CD34+CD38−CD90+CD45+) (hereafter termed CD90+HSPCs). Colony forming and stroma co-culture assays demonstrated that the hEB-OP9 CD90+HSPCs were able to differentiate into myelo-erythroid lineages and T-cells. However, when comparing CD90+HSPCs from hEB-OP9 to those from fetal liver (FL)—an in vivo source of HSCs—the former remained severely functionally limited in their proliferative potential and ability to differentiate into B-cells. To identify the basis of the proliferative and differentiation defects, we performed microarray analysis to define gene expression differences between CD90+HSPCs derived from hEB-OP9, FL, early 3–5 week placenta (PL) and an earlier stage of hESC differentiation (hEB). This analysis revealed establishment of the general hematopoietic transcription factor network (e.g. SCL, RUNX1, CMYB, ETV6, HOXB4, MYB), demonstrating the successful differentiation and identification of hematopoietic cells using our two-step culturing techniques and immunophenotype criteria. Moreover, evaluation of Spearman coefficients confirmed CD90+HSPCs isolated from hEB-OP9 culture were brought into closer resemblance of the hFL CD90+HSPCs as compared to to the developmentally immature hEB and hPL CD90+HSPCs. Encouragingly, hEB-OP9 CD90+HSPCs displayed downregulation of expression of genes related to hemogenic endothelium development associated with hEB and hPL while genes critical in HSPC function, including DNA repair and chromatin modification, were upregulated to levels comparable to hFL-HSPCs. However, a subgroup of FL HSPC genes could not be induced in hEB-OP9 HSPCs, including the HOXA cluster genes and BCL11A—implicated in HSC self-renewal and B-cell formation, respectively. Interestingly, absence of HOXA genes and BCL11A and poor proliferative potential were also observed in HSPCs from early placenta, suggesting these defects are not in vitro artifacts but instead reflect an inability of hEB-OP9 HSPCs to complete developmental maturation. To validate the necessity of HOXA genes and BCL11A in proliferation potential and multipotency, we next utilized shRNAs to target MLL—the upstream regulator of the HOXA cluster—, individual HOXA genes, or BCL11A in FL-HSPCs to test whether knockdown was sufficient to recapitulate the defects observed in hESC-derived HSPCs. Knockdown of HOXA7 resulted in the loss of CD34+ cells while HOXA9 shRNA-treated cells displayed a loss of more differentiated CD38hi cells. MLL knockdown depleted both CD38+ and CD34+ populations. BCL11A silencing resulted in the loss of B-cells. These studies identify HOXA genes and BCL11A as developmentally regulated genes essential for generating self-renewing, multipotent HSCs from pluripotent cells. Disclosures: No relevant conflicts of interest to declare.

Published
2012
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7. Discovery-based science education: functional genomic dissection in Drosophila by undergraduate researchers

Author

Kristin Spivey, Aneet Toor, Gerald B. Call, Brenda Hermogeno, Pamela Saarikoski, Qing Xu, Sheryllene Go, Vivek Singh, Brian Kirkpatrick, Bhavin Padhiar, Aram Shemmassian, Ramnik Singh, Steve Tovar, Sophia Wu, James Jen, Katrin Kahen, Courtney Gonzalez, Grant Alkin, Bassel Rifai, Poonam Desai, Damien Wood, Robert Kwak, Mariam Guirguis, Jayantha Thiyanaratnam, Preethi Poulose, Yuli Chang, Maggie Wells, Jamie L. Marshall, Aya Pusic, Marina Stavchanskiy, Thomas Kho, Nick Garrone, Jeyling Chou, Stephanie Calvillo, Charles Hu, Emily Vollmer, Winston Wu, Henry Lin, Sumit Datta, Leo Thai, Sheila Lezcano, Devon M Huff, Santino Laxamana, Meghann Ribbens, Mara Pavel-Dinu, Yein Kim, Yibing Chen, Eunha Kim, Nneka Orjiakor, Sarah Kim, Allison Milchanowski, Edwin Paz, Manyak Saakyan, Erin Marsh, Linda Kao, Russell Powell, Christopher N.H. Bui, Nikki Villarasa, Joy Wu, Eric Paul, Artemis Deravanesian, Aria Hong, Kha Nguyen, Akanksha Chhabra, Leena Tekchandani, Toni Lee, Utpal Banerjee, William R. Marrs, Elena Bibikova, Eric Lee, Lindsay Hovestreydt, Anna L. Abrams, Jordan Fabrikant, Joseph Cao, Chad Goffstein, So-Youn Lee, Daniel Chang, Will Yarosh, Peter Lin, Kosha Soneji, Christopher Lee, Thanh Luu, Katherine Fu, Maurine Tong, Amanda O'Donahue, Amanda Abramson, Desiree Rosselli, Gemma Lewis, Farid Jamshidian, George Yen, Jiong Chen, Amir Yavari, Yasaman Moshfegh, Amit Misra, Lephong Pham, Ernesto Nodado, Tanya Minasian, Ryan Hassid, Erika Stageberg, Stacy Chan, Cynthia Nguyen, Yuki Yamauchi, Marc Uemura, Janet Lee, Helena Minye, Aileen Chang, Alex Pavlenko, Kelly Trangsrud, Phyllis Gayda, Miles Morimoto, Kirsten Regalia, Jenny Chan, Ardy Davarifar, Shahbaz Farnad, Peter Dang, Daniel Solomin, Laura Yee, Jenny Anderson, Albert Cespedes, To Hang S Lee, Julie Luu, Jessica Murray, Allen Bookatz, Keenan Bashour, Joo Choi, Adam D. Langenbacher, Emil Kohan, Amy M. Chan, Sarah Min, Melissa M. Kelley, Miriam Segura, Elsa Beyer, Sarah Phaklides, Natalie Buu, Emily Weiss, Mary Unkovic, Julie Hong, Emily Skinner, Farnaz Shadpour, Wah-Yung Tsang, Eddie Garcia, Divi Ramola, Latiffe Amado, Srpouhi Gasparyan, Sarah Brewer, Kevin Yackle, and Ndidi Onugha

Subjects
Discovery science, Genetics, General Immunology and Microbiology, QH301-705.5, General Neuroscience, Genomics, In vivo analysis, Biology, Development, Genetics/Genomics/Gene Therapy, Data science, Science education, Genome, General Biochemistry, Genetics and Molecular Biology, Community Page, ComputingMilieux_COMPUTERSANDEDUCATION, Identification (biology), Drosophila, Biology (General), General Agricultural and Biological Sciences, Curriculum, Functional genomics
Abstract

The excitement of scientific research and discovery cannot be fully conveyed by didactic lectures alone. Several recent initiatives and proposals, therefore, have supported a more participatory, discovery-based instruction for undergraduate science education [1,2]. In functional genomics, we have found an ideal platform to simultaneously benefit students and contribute to scientific discovery. The sequencing of eukaryotic genomes has facilitated the identification of complete sets of genes in humans and model genetic organisms. This has allowed many forms of high-throughput analyses of transcriptional profiles, protein interactions, structural motifs, and even genome-wide knock-downs in cell lines or in selected organisms. However, one of the best tools to provide functional information about gene action— obtaining in vivo evidence about the phenotype resulting from heritable loss of function—is difficult and less amenable to high-throughput research. We were able to achieve a large-scale in vivo analysis with a significant number of undergraduate students at UCLA, called the UCLA Undergraduate Consortium for Functional Genomics. This work, a practical manifestation of policy positions proposing discoverybased education, is described in summary form here (and in Box 1) and in detail online at http://www.bruinfly.ucla.edu. This effort combines professional-quality research with a strategy for research-based undergraduate education.

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