Nathaniel Hogrebe, PhD has always had an interest in science, and now, as a junior faculty member in the Millman Lab, he has steadily built a career as a leader in diabetes research, working closely with Dr. Millman to pioneer cutting-edge research in stem cell-derived islets (SC-islets).
Throughout his education, Dr. Hogrebe knew that rather than being a traditional biologist, he wanted to work with his hands and solve real-world problems, which led him to the engineering aspect of his work. “I wanted to make something,” he said. “Engineering was attractive because you apply basic science to real-world problems. You make a product that can actually help people.” With a parallel interest in biology, merging the two became a natural career path for Dr. Hogrebe.
During his graduate training at The Ohio State University, Dr. Hogrebe worked with mesenchymal stem cells (MSCs), which can differentiate into several lineages including adipocytes (fat cells), osteoblasts (bone cells), and chondrocytes (cartilage cells). He studied how different cues from the physical microenvironment surrounding a cell, such as substrate stiffness and adhesiveness, influenced their differentiation into these cell types. In particular, mimicking properties of the microenvironment where each cell type is naturally found in the body facilitated differentiation into that cell type. These studies have translated into the work he does today in the Millman lab, studying how the cell microenvironment and its effects on the actin cytoskeleton influence cell fate choice during the differentiation of human pluripotent stem cells (hPSCs) to SC-islets.
After graduating with his Ph.D. in Biomedical Engineering in 2016, Dr. Hogrebe came to WashU Medicine as a Postdoctoral Research Fellow in Dr. Jeffrey Millman’s laboratory. Although he wasn’t entirely sure about his future being in industry or academia, his career and interests evolved naturally, and he realized he liked the research aspect of academia. He was promoted to a research track Instructor of Medicine in February 2023 and plans to start his own lab in the division while maintaining his close partnership with Dr. Millman.
Throughout his time at WashU, Dr. Hogrebe has made significant strides in enhancing the generation of insulin-producing islets from hPSCs for the treatment of diabetes. His research has revealed that the state of the actin cytoskeleton within a cell plays a crucial role in cell fate decisions throughout the differentiation of hPSCs to SC-islets. By controlling cytoskeletal state through either soluble small molecules or by modulating physical culture conditions at specific time points during the differentiation, SC-islet generation can be drastically improved. These enhancements lead to a higher percentage of mature β cells that secrete more insulin and rapidly reverse hyperglycemia when transplanted into severely diabetic mice. Notably, this approach also corrects differentiation issues in hPSC lines that typically struggle to produce pancreatic islets, further underscoring the importance of cytoskeletal signaling in stem cell differentiation strategies.
Dr. Hogrebe aims to continue improving SC-islets for future clinical applications. A critical next step is scaling up the manufacturing of SC-islets. “We have these cells that function very well,” he explained. “At this point, they’re good enough to cure a person, but in order to scale this therapy so that hundreds of people can get it – which is still small compared to how many people need it – we will need to make trillions of cells. This is a big logistical and technical issue on how to make that many.” The goal is to develop processes that can overcome this challenge and to eventually make
cells that meet Good Manufacturing Process (GMP) standards so that they are suitable for transplantation into human patients.
Dr. Hogrebe’s favorite part of his research, particularly in the Millman lab, is its translational nature. “It’s exciting to think that the research that I do in the lab now can accelerate the progress of this cell therapy so that it can eventually provide a real functional cure for diabetic patients.”
Dr. Hogrebe encourages younger trainees to continue to enhance both their technical and soft skills throughout their training to become well-rounded scientists. Furthermore, he advises them to prioritize conducting impactful science and producing quality work rather than fixating on the next promotion or job advancement. “If you do quality science, everything else falls into place,” he asserts.