To date our program has supported 21 trainees, of which eight have received their Ph.D. and 13 are completing their doctoral training. The majority of graduates from this relatively new program are now postdoctoral researchers at academic institutions. One program graduate is employed as a Clinical Development Engineer developing minimally invasive surgical systems, and one is a Health and Science Writer at a prominent university hospital.
Diversity is a core value of the University of California. Our program shares this commitment to recruiting, training and promoting the careers of the most talented students from all backgrounds.
Additional graduate fellowships awarded to trainees of this program include:
- GEM University Fellowship (1)
- NSF Graduate Research Fellowship (7)
- UC Berkeley Chancellor’s Fellowship (3)
- Jack Kent Cooke Foundation Fellowship (1)
Since the program’s inception in 2011, current and former trainees have co-authored 23 journal articles based on their thesis research. Recent examples of trainee publications include:
“Injury Activates Transient Olfactory Stem Cell States with Diverse Lineage Capacities”
Gadye L**, Das D, Sanchez MA, Street K, Baudhuin A, Wagner A, Cole MB, Choi YG, Yosef N, Purdom E, Dudoit S, Risso D, Ngai J, Fletcher RB. Cell Stem Cell. 2017 Dec 7;21(6):775-790. PMID: 29174333; PMCID: PMC5728414; DOI:10.1016/j.stem.2017.10.014
Tissue homeostasis and regeneration are mediated by programs of adult stem cell renewal and differentiation. However, the mechanisms that regulate stem cell fates under such widely varying conditions are not fully understood. Using single-cell techniques, we assessed the transcriptional changes associated with stem cell self-renewal and differentiation and followed the maturation of stem cell-derived clones using sparse lineage tracing in the regenerating mouse olfactory epithelium. Following injury, quiescent olfactory stem cells rapidly shift to activated, transient states unique to regeneration and tailored to meet the demands of injury-induced repair, including barrier formation and proliferation. Multiple cell fates, including renewed stem cells and committed differentiating progenitors, are specified during this early window of activation. We further show that Sox2 is essential for cells to transition from the activated to neuronal progenitor states. Our study highlights strategies for stem cell-mediated regeneration that may be conserved in other adult stem cell niches.
“hPSC-Derived Striatal Cells Generated Using a Scalable 3D Hydrogel Promote Recovery in a Huntington Disease Mouse Model”
Adil MM, Gaj T, Rao AT, Kulkarni RU, Fuentes CM**, Ramadoss GN, Ekman FK, Miller EW, Schaffer DV. Stem Cell Reports. 2018 May 8;10(5):1481-1491. PMID: 29628395; PMCID: PMC5995679; DOI: 10.1016/j.stemcr.2018.03.007.
Huntington disease (HD) is an inherited, progressive neurological disorder characterized by degenerating striatal medium spiny neurons (MSNs). One promising approach for treating HD is cell replacement therapy, where lost cells are replaced by MSN progenitors derived from human pluripotent stem cells (hPSCs). While there has been remarkable progress in generating hPSC-derived MSNs, current production methods rely on two-dimensional culture systems that can include poorly defined components, limit scalability, and yield differing preclinical results. To facilitate clinical translation, here, we generated striatal progenitors from hPSCs within a fully defined and scalable PNIPAAm-PEG three-dimensional (3D) hydrogel. Transplantation of 3D-derived striatal progenitors into a transgenic mouse model of HD slowed disease progression, improved motor coordination, and increased survival. In addition, the transplanted cells developed an MSN-like phenotype and formed synaptic connections with host cells. Our results illustrate the potential of scalable 3D biomaterials for generating striatal progenitors for HD cell therapy.
“The mitochondrial unfolded protein response is activated upon hematopoietic stem cell exit from quiescence”
Mohrin M, Widjaja A**, Liu Y, Luo H, Chen D. Aging Cell. 2018 June;17(3):e12756. PMID: 29575576; PMCID: PMC5946069; DOI: 10.1111/acel.12756.
The mitochondrial unfolded protein response (UPRmt ), a cellular protective program that ensures proteostasis in the mitochondria, has recently emerged as a regulatory mechanism for adult stem cell maintenance that is conserved across tissues. Despite the emerging genetic evidence implicating the UPRmt in stem cell maintenance, the underlying molecular mechanism is unknown. While it has been speculated that the UPRmt is activated upon stem cell transition from quiescence to proliferation, the direct evidence is lacking. In this study, we devised three experimental approaches that enable us to monitor quiescent and proliferating hematopoietic stem cells (HSCs) and provided the direct evidence that the UPRmt is activated upon HSC transition from quiescence to proliferation, and more broadly, mitochondrial integrity is actively monitored at the restriction point to ensure metabolic fitness before stem cells are committed to proliferation.
“Protein Diffusion from Microwells with Contrasting Hydrogel Domains”
Su EJ, Jeeawoody S**, Herr AE. APL Bioengineering. 2019 June;3(2):026101. PMID: 31069338; PMCID: PMC6481738; DOI: 10.1063/1.5078650
Understanding and controlling molecular transport in hydrogel materials is important for biomedical tools, including engineered tissues and drug delivery, as well as life sciences tools for single-cell analysis. Here, we scrutinize the ability of microwells-micromolded in hydrogel slabs-to compartmentalize lysate from single cells. We consider both (i) microwells that are “open” to a large fluid (i.e., liquid) reservoir and (ii) microwells that are “closed,” having been capped with either a slab of high-density polyacrylamide gel or an impermeable glass slide. We use numerical modeling to gain insight into the sensitivity of time-dependent protein concentration distributions on hydrogel partition and protein diffusion coefficients and open and closed microwell configurations. We are primarily concerned with diffusion-driven protein loss from the microwell cavity. Even for closed microwells, confocal fluorescence microscopy reports that a fluid (i.e., liquid) film forms between the hydrogel slabs (median thickness of 1.7 μm). Proteins diffuse from the microwells and into the fluid (i.e., liquid) layer, yet concentration distributions are sensitive to the lid layer partition coefficients and the protein diffusion coefficient. The application of a glass lid or a dense hydrogel retains protein in the microwell, increasing the protein solute concentration in the microwell by ∼7-fold for the first 15 s. Using triggered release of Protein G from microparticles, we validate our simulations by characterizing protein diffusion in a microwell capped with a high-density polyacrylamide gel lid (p > 0.05, Kolmogorov-Smirnov test). Here, we establish and validate a numerical model useful for understanding protein transport in and losses from a hydrogel microwell across a range of boundary conditions.
“Structure of a P Element Transposase-DNA Complex Reveals Unusual DNA Structures and GTP-DNA Contacts”
Ghanim GE**, Kellogg EH, Nogales E, Rio DC.. Nature Structural & Molecular Biology. 2019 October 28. PMID: 31659330; DOI: 10.1038/s41594-019-0319-6.
P element transposase catalyzes the mobility of P element DNA transposons within the Drosophila genome. P element transposase exhibits several unique properties, including the requirement for a guanosine triphosphate cofactor and the generation of long staggered DNA breaks during transposition. To gain insights into these features, we determined the atomic structure of the Drosophila P element transposase strand transfer complex using cryo-EM. The structure of this post-transposition nucleoprotein complex reveals that the terminal single-stranded transposon DNA adopts unusual A-form and distorted B-form helical geometries that are stabilized by extensive protein-DNA interactions. Additionally, we infer that the bound guanosine triphosphate cofactor interacts with the terminal base of the transposon DNA, apparently to position the P element DNA for catalysis. Our structure provides the first view of the P element transposase superfamily, offers new insights into P element transposition and implies a transposition pathway fundamentally distinct from other cut-and-paste DNA transposases.