City of Hope’s Train, Educate and Accelerate Mastery of Stem cell research (TEAMS) program was built around four key areas of regenerative medicine research: Cancer Stem Cells, Hematopoietic Stem Cells, Tissue-Specific Stem Cells and Human Pluripotent Stem Cells. We recruited well-qualified mentors to support the training of our 14 CIRM TEAMS trainees. Each of the trainees was assigned a project that allowed them to develop the conceptual, technical and ethical skills to explore the topic.
Within the field of Cancer Stem Cells we had four trainees. One trainee focused on developing in vitro growth conditions to optimize expansion of luminal epithelial cells and c-KIT+ progenitor cells to explore the early stages of breast cancer. A second trainee focused on developing a fluorescent marker to allow for the characterization of a CAR-T cell population as it interacts with the targeted brain tumor. Two students focused on establishing transgenic mouse models to explore the impact of androgen receptor, hepatocyte growth factor and human c-MET on the development of prostate cancer tumors.
Within the field of Hematopoietic Stem Cells one trainee explored the impact of SGF29, a protein that recognizes methylated histones and modulates transcription, in leukemic cancer stem cells. To approach this question a CRISPR-Cas9 approach was used to delete the SGF29 gene and assess its impact on cellular growth.
Four trainees worked within the field of Tissue-Specific Stem Cells. One student explored the impact of modulating the cohesion complex on the growth and behavior of insulin-producing -cell. Knocking out one of the cohesin complex components, SMC3, allowed the trainee to explore the impact of cohesin during early neonatal development and later as the mouse develops into an adult. The trainee discovered that cohesin is a critical component of the replication process, which is the primary mechanism of -cell mass expansion. A second trainee examined the relationship between aging and the activation of adipocyte progenitor cells. This analysis led to the discovery of a population of preadipocyte cells whose gene expression is remodeled in an age-specific fashion. A third trainee looked at the relationship between -cell and endothelial cell dysfunction and the role of endothelial Argonaute 1(AGO1) in this process. Specifically, the trainee looked at the ability of an endothelial cell AGO 1 gene knockout to rescue streptozotocin-induced damage in female mice. This was assayed by looking at insulin sensitivity, glucose regulation, and body weight. Our fourth trainee participated in a project directed at modifying oleanolic acid to improve its water solubility and improve its absorptive characteristics. The trainee focused on taking analogs of oleanolic acid and analyzing their Octanol-Water Partition Coefficient using High-Performance Liquid Chromatography. The ultimate goal of this research is to develop analogs of oleanolic acid to take advantage of its robust anti-inflammatory properties for clinical applications.
With the field of Human Pluripotent Stem Cells we supported four trainees. Our first trainee focused on the impact of pseudouridine in coding and noncoding RNAs as an effector of glioblastoma stem cells (GSC) and the development of glioblastoma multiforme brain tumors. Using CRISPR-Cas9 the trainee mutated specific pseudoruridylation sites in noncoding RNAs of interest in GSCs. These modifications led a reduction of cellular growth as compared to a control population of untreated cells. A second trainee examined the role of Sae2 in DNA replication, a critical step in growth and self-renewal of pluripotent stem cells. Understanding the activity of this gene will allow for an improved understanding of how cells can survive DNA damage leading to genomic rearrangements that support the initial stages of tumorgenesis and subsequent cancer development. Our third trainee in this group focused on the generation of human artificial thymic organoids (ATO) from umbilical cord blood derived hematopoietic stem cells to allow for the study of T cell development. Using ATOs developed from different cell lines the trainee assessed the ability to support CD34+ differentiation. The ultimate goal is to use ATOs to develop cancer fighting T cells for immunotherapy applications. Our final student worked to introduce a “suicide gene” construct into engineered in iPSCs for the generation of the insulin-producing -cell to treat type 1 diabetes patients. The suicide gene would allow for the removal of undifferentiated iPSCs that could potentially become tumors following transplantation.
This summer our CIRM TEAMS cohort has successfully delved into a wide range of topics impacting regenerative medicine and stem cell biology. We are confident that this experience has created a platform for them to launch into careers that will impact these fields of research in the future.
Reporting Period:
Year 2
In the pursuit of pioneering scientific advancements, a group of devoted researchers and their CIRM trainees have explored the mysteries of the human body with a goal of developing groundbreaking therapies and unraveling the complex interactions occurring within our cells. These researchers, supported by the California Institute for Regenerative Medicine are pushing the frontiers of knowledge and innovation, and creating hope for countless individuals affected by various health conditions. The endeavors under this award during the reporting period have manifested substantial progress in diverse scientific domains, providing novel insights and fostering the development of potentially transformative therapeutic strategies.
The expansive world of scientific research constantly nurtures an environment ripe with discovery and innovation. Researchers of varying experience levels, united in their passion and dedication, are exploring fundamental questions in biology, thereby contributing significantly to the ever-growing body of knowledge across multiple disciplines.
• In the Arthur Riggs Diabetes and Metabolism Research Institute, REDACTED, mentored by Dr. Meirigeng Qi and Amber Tucker, was instrumental in unveiling insights into intra-pancreatic tissue-derived mesenchymal stromal cells. Her pivotal work contributed to potential therapeutic strategies for Type 1 diabetes and propelled the field of translational research and cellular therapies forward.
• Similarly, REDACTED, working under the guidance of Dr. Hsun Teresa Ku and Janine Quijano, Ph.D., has opened up new pathways by studying ductal progenitor cell differentiation after pancreas injury, which is pivotal for developing potential treatments.
• REDACTED, who focused her research exploring metabolism and aging, under the expert guidance of Drs. Qiong Wang and Guan Wang, investigated the complex relationships between adipose progenitor cells, aging, and obesity, thus significantly enriching our understanding of metabolic disorders.
• REDACTED, working with Dr. Enrique Montero and Isaac Garcia in the domain of oncological innovations and precision medicine, is at the forefront of innovating CAR T-cell efficacy, paving the way for refined approaches to combat glioblastoma.
• Within the neurological field, REDACTED, mentored by Dr. Qiang Lu and Cesar Gonzalez, has ventured into exploring the landscapes of Zeb1 and glioblastoma microenvironments, providing new therapeutic insights into aggressive neoplasms and malignant brain cancers.
• REDACTED, under the guidance of Dr. Zhaohui Gu and Alex Chassiakos, contributed to potential advancements in leukemia research through his exploration of B-cell development using computational analysis.
• Molecular exploration by REDACTED, REDACTED, and REDACTED uncovered the intricacies of cellular interactions and regeneration in metabolic and cardiac domains under the guidance of their respective mentors, Drs. Sangeeta Dhawan, Sneha Varghese, Yingfeng Deng, and Ling Fu.
• REDACTED, working with Dr. Zhao V. Wang and Yin Wang, Ph.D., delved deeply into assessing the role of nucleotide balance in cardiac regeneration, aiming to develop therapeutic strategies for enhanced cardiac repair post-injury.
• REDACTED, focusing on arterial research and non-invasive therapies was mentored by Dr. Zhen Chen and Dr. Naseeb Malhi, exploring non-invasive treatments and novel insights into advanced medical interventions for arterial diseases.
• REDACTED, under the mentorship of Dr. Yanhong Shi, in the field of neurology, constructed human brain models to explore Alzheimer's disease, offering innovative insights and hope in the sphere of neurodegenerative disorders.
These exceptional students, each in their unique domains, participated in scientific exploration, which moved the frontiers of knowledge and innovation forward.
Reporting Period:
Year 3
During this reporting period, our CIRM trainees made progress in advancing our understanding of cancer, diabetes, and regenerative medicine. Supported by the CIRM TEAMS funding, the boundaries of scientific knowledge were advanced with the hope of improving patient care in the future.
In cancer research, Redacted, mentored by Dr. Behnam Badie, worked to improve treatment strategies for glioblastoma. He focused on developing and testing RAGE inhibitors, to modulate the NF-κB signaling pathway while preserving immune responses. Redacted’s findings could contribute to more effective therapeutic approaches for treating this cancer. Redacted, mentored by Dr. Andrei Rodin, developed an interpretable, information-theory-based method to analyze spatial gene expression in glioblastoma. Her work provided insights into tumor microenvironments and stem cell dynamics.
Redacted, working with Dr. Russell Rockne, investigated the role of extracellular vesicles (EVs) and their impact on CAR-T cell therapies. His work seeks to understand how EVs influence CAR-T cell effectiveness and to develop mathematical models to enhance the therapeutic potential of CAR-T therapies against glioblastoma. Redacted, mentored by Dr. Saul Priceman, explored how modifying the bead-to-T cell ratio during CAR-T cell manufacturing can prevent overactivation and off-target effects. Her work aims to improve its therapeutic efficacy, complementing Isaac’s efforts to enhance CAR-T therapies in cancer treatment.
In cancer biology, Redacted, mentored by Dr. Robert J. Hickey, explored the selective inhibition of the cancer-associated isoform of PCNA. His research assessed the efficacy of the caPCNA-selective inhibitor AOH1996 against various cancer types. Redacted, working with Dr. Qiang Lu, explored the role of Zeb1 in gliogenesis during early brain development. Her work may provide valuable insights that could inform therapies for both brain cancers and neurodegenerative diseases.
In diabetes research, Redacted, mentored by Dr. Zuoming Sun, focused on the role of Th17 cells in the progression of Type 1 Diabetes (T1D). She demonstrated that treatment with a RORγt inhibitor reduced diabetes incidence, highlighting the therapeutic potential to mitigate T1D. Redacted, mentored by Dr. Ben Shih, worked on enhancing the differentiation of human pluripotent stem cells into pancreatic islet cells. Kira’s research revealed that the cell adhesion protein Ctnna1 is essential for islet aggregation and function and promotes cholesterol biosynthesis. Her ongoing investigation of Srebf2, a key regulator of CBS, may provide insights to improve stem cell-based therapies for diabetes. Together, Kira’s and Redacted’s work advances our understanding of T1D mechanisms and potential therapies. Redacted, working with Dr. Jiing-Kuan Yee, built on these efforts by focusing on improving the safety and efficacy of SC-islet transplantation for T1D. Her research aims to minimize risks of teratoma formation and immune rejection by incorporating genetic modifications into stem cell-derived islets.
In Type 2 Diabetes (T2D) research, Redacted, mentored by Dr. Sangeeta Dhawan, investigated the DNA damage vulnerability of pancreatic alpha and beta cells. His findings that alpha cells are more susceptible to damage under metabolic stress compared to beta cells could inform therapeutic strategies aimed at protecting these critical cells in T2D patients. Similarly, Redacted, working with Dr. Yingfeng Deng, explored how endoplasmic reticulum (ER) stress affects beta cell survival in T2D. Her research seeks to determine whether beta cell loss due to ER stress is reversible. Redacted’s studies provide valuable insights into the cellular mechanisms underlying T2D.
In regenerative medicine, Redacted, mentored by Dr. Teresa Ku, explored the potential of ductal cell-derived beta cells for beta cell replacement therapy in T1D. Her work evaluated compounds that promote beta cell proliferation. Redacted mentored by Dr. Zhao Wang, helped establish a novel in vitro diabetic cardiomyopathy (DCM) model using human induced pluripotent stem cell-derived cardiomyocytes. This model will be used to study the pathological mechanisms of DCM. This work will accelerate drug discovery, uncover new DCM-related signaling pathways, and improve clinical outcomes for patients with diabetes.
Finally, Redacted applied machine learning techniques to enhance the characterization of extracellular vehicles (EVs). His work, combining advanced imaging methods with artificial intelligence, aims to improve the identification and analysis of EVs.
Together, these students have made significant contributions to the fields of cancer, diabetes, and regenerative medicine. Their dedication and innovative research underscore the potential for future therapeutic breakthroughs, offering hope to countless individuals affected by these diseases.
Grant Application Details
Application Title:
Train, Educate, and Accelerate Mastery of Stem cell research (TEAMS) program
Public Abstract:
It is well documented that trainees from groups underrepresented in the STEM fields leave the research workforce pipeline, with many progressively losing interest in research-intensive careers. To overcome this, we will leverage our institution’s long-standing success in education and training toward engaging underrepresented individuals in the field of regenerative medicine. The Train, Educate, and Accelerate Mastery of Stem cell research (TEAMS) program’s primary goal is to develop and maintain a robust pipeline of students excited about regenerative medicine research to become the next generation of researchers. We will inspire, educate, and motivate qualified candidates from southern California’s diverse populations, enabling them to master critical regenerative medicine knowledge and skills using a multidisciplinary approach. Under the umbrella of a long-standing, renowned summer academy, the 10-week TEAMS program will select 10 high school students (over the age of 16) to participate in a 10-week program that places trainees in 10 (of 23 potential) laboratories focused on regenerative medicine research. Our goal is for TEAMS to become a focal point for mentoring and training a diverse pipeline of regenerative medicine researchers to address disparities in its application. Strong mentorship, especially through formalized programs, can enable trainees to navigate a research career pathway and strengthen their commitment to a regenerative medicine career as early as possible.
Our institution is home to a diverse group of researchers who are exploring a broad array of regenerative medicine topics, and actively promotes diversity, equity, and inclusion in our workforce. Our mentors have historically embraced the opportunity to host CIRM-SPARK trainees, ensuring a superlative first-hand experience in pursuing a hypothesis-driven, regenerative medicine-focused research project. Early exposure to biomedical research allows trainees to fully appreciate all aspects of the scientific process, including developing a hypothesis, designing experiments, performing experiments, gathering and analyzing data, and drawing conclusions. By coupling this with clinical interactions, training in cutting-edge core facilities, participation in an established personal and professional development program, and community outreach opportunities, we will ensure that each TEAMS trainee is inspired by the untapped potential of biomedical research. Together, these experiences will provide a broad educational foundation as well as stimulate an interest in pursuing regenerative medicine-based research in the future.
We have a robust history of supporting training of this kind, exemplified by our summer academy, a recently concluded CIRM-SPARK program, and other federally funded programs to engage students in the research pipeline. Many alumni of these programs (61.5%) currently remain in a science-based career pipeline including biomedical research and medicine.
Statement of Benefit to California:
California leads the world in regenerative medicine discovery. Despite this significant accomplishment, our regenerative medicine treatments have been minimally evaluated in people of color. Most clinical trial participants are non-Hispanic European-Americans. Among researchers, disparities in training occur throughout the entire regenerative medicine research pipeline. Latinx/Hispanic- or African-Americans account for only a small number of research scientists and <2% of physicians conducting clinical trials.
The population of southern California represents a melting pot that is culturally and racially diverse. A 2019 population estimate reported Los Angeles County to have a population of 10,039,107, which included 26% white, 48.6% Hispanic, 15% Asian, 9% African American, and 2% American Indian/Alaska Native/Pacific Islander, with similar demographics in neighboring counties. Located in southern California, our proposed Train, Educate, and Accelerate Mastery of Stem cell research (TEAMS) program recognizes our opportunity to enhance the scientific workforce by reducing the barriers to success for groups of people who face unique challenges in entering the regenerative medicine field. The benefits of diversifying the workforce include promoting innovation and global competitiveness and increasing the likelihood that biomedical advances will benefit our diverse population, including medically underserved groups.
To promote the development of a diverse workforce that reflects our state and local communities, we will offer local high school students the chance to engage in science as a hands-on experience rather than as a lecture and textbook exercise. The TEAMS program will leverage our majority-minority community and our institution’s diversity training programs and world-renowned regenerative medicine discovery resources. Trainees will gain a general understanding of a range of biomedical topics and expand their personal and professional development under the guidance of our dedicated faculty and staff. Carrying out experiments in a model system is not limited to simply applying a protocol to arrive at a particular endpoint, it is also necessary to understand both the ethical implications of the work and the potential impact it may have on patients. Thus, TEAMS trainees will also explore bioethical issues surrounding regenerative medicine, including representation and disparities. Our institution is nationally recognized for our clinical application of regenerative medicine in cancer and diabetes, and trainees will also interact with our clinicians and patient advocates working in the areas of bone marrow transplant, islet cell transplantation, and CAR T cell therapy. This opportunity will provide trainees with a unique perspective of the very real impact that regenerative medicine-based therapies have on the lives of patients. Our goal is to build a diverse regenerative medicine pipeline and address disparities in our community.
