In the summer of 2022, CIRM SPARK interns at Children's Hospital Los Angeles performed research in three main areas:
1. The effectiveness of amniotic fluid stem cell-derived extracellular vesicles in rescuing glomerular endothelial cells in Alport Syndrome (AS) (two students). These students were studying how to reverse AS-associated damage to "glomeruli," complex structures made up of blood vessels that perform filtration in the kidneys. AS is a form of chronic kidney disease, and damage to the glomeruli is a key part of the pathology of this disease. The interns tested whether products released by stem cells isolated from amniotic fluid can protect against or repair the damage to these critical structures in AS.
2. Mechanisms controlling regeneration of the intestinal lining after an injury (two students). These students tested whether proteins that seal the spaces between cells of the intestinal lining (components of the cell-cell connections called "tight junctions") are required for wound repair and regeneration of that tissue after an injury. This regenerative process is potentially compromised in inflammatory bowel disease, a chronic incurable condition that affects roughly 1 in 200 Americans.
3. The effects of COVID-19 on insulin-producing pancreatic beta cells (four students). These students tested whether Sars-CoV-2 infects the pancreas and damages the beta cells that produce insulin, and whether vaccination prevents against beta cell dysfunction after COVID-19.
All of the CIRM SPARK interns successfully completed their projects and wrote abstracts based on their work. They presented their work as posters at the SPARK symposium in Oakland and oral presentations at a symposium at Children's Hospital Los Angeles.
Reporting Period:
Year 2
In the summer of 2023, CIRM SPARK interns at Children's Hospital Los Angeles performed research in four main areas:
1. The role of Notch3 signaling in heart regeneration in zebrafish. Interns demonstrated that Notch3 levels are elevated in the regenerating portion of a zebrafish heart, and then used an inducible expression system to test whether increased Notch3 would accelerate healing. This is of interest since understanding how fish regrow their heart after injury could lead to regenerative medicine approaches for heart attacks in humans.
2. Regulation of the colonic stem cell niche. Interns tested the role of signaling pathways activated by the growth factor neuregulin-1 in the development of support cells necessary for stem cell survival in the gut. Understanding these mechanisms better could lead to regenerative medicine based treatments for inflammatory bowel disease, chemotherapy-induced enteritis, and other disorders.
3. Effects of a pathogenic BEST1 gene mutation on the retinal pigment epithelium (RPE). The RPE is a critical component of the eye that supports the retina's health through several mechanisms. Interns on this project used induced pluripotent stem cell-derived RPE culture models to test whether mutations in BEST1 that cause macular degeneration affect the integrity of the RPE.
4. Development of vagus nerve connections to sensory cells in the gut. Interns tested whether gut-vagus circuits that sense satiety are altered after early-life exposure to a high-fat Western diet. Specifically, they tested whether this early-life exposure leads to alterations in adulthood of levels of receptors for hormones that signal satiety.
All of the CIRM SPARK interns successfully completed their projects and wrote abstracts based on their work. They presented their work as posters and short talks at the SPARK symposium in Los Angeles and oral presentations at a symposium at Children's Hospital Los Angeles.
Reporting Period:
Year 3
In the summer of 2024, CIRM SPARK interns at Children's Hospital Los Angeles performed research in four main areas:
1. Regulation of the intestinal stem cell niche. Two interns tested the relative roles of the growth factors neuregulin-1 and neuregulin-2 in driving regenerative responses and maintaining progenitor cell identity in the intestinal epithelium. Four other interns worked on the interaction between inflammation and stem cell differentiation in the colonic epithelium, testing the change in stem cell proliferation and differentiation patterns in the colonic crypt at different stages of acute and chronic inflammation. Understanding these mechanisms better could lead to regenerative medicine based treatments for inflammatory bowel disease, chemotherapy-induced enteritis, and other disorders.
2. Optimizing podocyte differentiation from amniotic fluid stem cells. In this project, interns studied methodologies and small molecule treatments that could be used to optimize the generation of mature kidney podocytes from amniotic fluid stem cells ex vivo. Since podocytes are critical for kidney function, are lost in chronic kidney disease (CKD), and cannot be replaced by the organism under normal circumstances, this work has strong potential for regenerative medicine applications for CKD.
3. Stem-cell derived extracellular vesicles (EVs) as cell-derived therapy for CKD. This project focused on whether EVs from amniotic fluid stem cells could protect mitochondrial function and survival of glomerular endothelial cells, another essential component of the kidney filtration system that is damaged in CKD.
4. Methods to isolate cancer stem cells from Wilms Tumor (WT). The interns on this project learned how to generate and deliver "Smartflares," which label RNA to allow live cell sorting based on gene expression. They used the platform to isolate the SIX2+ cancer stem cells from cultured WT. As purifying the initiating stem cells has been a major roadblock in WT research, this opens up a method for understanding the transcriptomics and cancer stem cell behavior in WT, with an eye towards developing new therapeutics.
All of the CIRM SPARK interns successfully completed their projects and wrote abstracts based on their work. They presented their work as posters and short talks at the SPARK symposium in Riverside and oral presentations at a symposium at Children's Hospital Los Angeles.
Grant Application Details
Application Title:
Stem Cell and Regenerative Medicine Summer Internships for High School Students from Under-Served Communities
Public Abstract:
This proposal is for a summer internship program that provides laboratory research experience in regenerative medicine and stem cell biology to high school students from populations that are traditionally under-represented in biomedical science careers. Rising seniors from under-served groups will be placed (8-12 students per year) in paid internships for the summer, conducting original research under the direction of established scientists and physician-scientists. Through mentored hands-on experimentation, the students will learn how basic research in stem cell biology can drive the discovery of new ways to detect and treat disease. In addition to the hands-on work in the labs, interns will learn to read and interpret the scientific literature, write a scientific abstract, and orally communicate their research at a formal symposium that caps the summer program. They will attend a daily didactic workshop in disease-focused stem cell concepts, and work with professional college counselors to build academic and professional skills to ensure that after their senior year they will matriculate to an undergraduate institution suited to preparing them for a career in science. Overall, this program is designed to increase the number of students from under-served backgrounds who pursue research careers, thus building a more diverse stem cell biology and regenerative medicine workforce of the future.
Statement of Benefit to California:
Our high school internship program was established with the goal of increasing diversity in the pipeline to biomedical science, and in particular stem cell biology careers. The program provides students from backgrounds that are under-represented in science and medicine with the opportunity to learn hands-on laboratory-based stem cell research and receive professional college preparation counseling. Through these efforts we aim to (1) encourage students to embark on the path to become scientists or physician-scientists with a focus on careers in regenerative medicine, (2) provide them with laboratory research experience that will both grow their interest in science and make them competitive for student research opportunities in college, and (3) assist them in gaining admission to outstanding colleges and universities that will prepare them for advanced study and potential careers in stem cell biology and regenerative medicine. Benefits to California include:
1. Increasing interest in regenerative medicine careers among students from backgrounds that are chronically under-represented in stem cell research.
California is the most diverse state in the USA, with for example ~39% of the populace identifying as Latinx/Hispanic and another ~6% identifying as Black/African-American. This diversity of California’s population is not, however, reflected in the scientific workforce. Empowering Latinx/Hispanic, Black/African-American, and other minority students in California to see themselves as future scientists (and giving them the tools to begin pursuing this goal) thus represents benefit for the state both in terms of expanding the available scientific workforce and in working towards removing structural barriers that prevent equitable opportunity for these students.
2. Developing and training a cohort of scientific mentors who are ready to promote diversity, equity, and inclusion in the scientific community in California.
A challenge for efforts to remove barriers to participation in scientific fields is overcoming the inertia of the status quo/established culture of the scientific community. By engaging successful stem cell researchers in the process of mentoring would-be scientists from under-served communities, we hope to normalize the idea that removing these barriers and reaching out to these students is an important part of a practicing scientist's mission and citizenship.
3. Strengthening connections and understanding between California stem cell researchers and the community at large.
The last few years have seen an erosion in public trust in scientific expertise in the USA, with disastrous public health consequences. Better communication and connection between the academy and the community is essential to reverse this trend. This goal will be served by generating cohorts of students who have seen stem cell research “from the inside.”
