Kotaro Sasaki, MD, PhD, joined Penn Vet in 2018 and is currently the Richard King Mellon Associate Professor of Biomedical Sciences. His lab is primarily interested in understanding how human urogenital and reproductive organs develop and using this knowledge to develop stepwise and directional induction schemes to generate such organs in vitro from human induced pluripotent stem cells.
Dr. Sasaki became interested in biomedical research in 2001 as a second-year medical student at Hokkaido University when he attended an immunology lecture given by Professor Takashi Nishimura, who fervently explained that through an in-depth understanding of how immune cells work, scientists are now on the cusp of curing cancers through the use of engineered immune cells. Struck by such a transformative idea, Dr. Sasaki joined Dr. Nishimura’s lab as a visiting scholar. During this period, he discovered that the T cell adhesion molecule very late antigen-2 (VLA-2) is differentially expressed between polarized type-1 and type-2 T cells. After briefly working as an intern in the emergency department of the International Medical Center of Japan, Dr. Sasaki moved to the US and joined the immunology department at the University of Pittsburgh under the supervision of Drs. Walter Storkus and Hideho Okada. As a postdoctoral fellow, he discovered that VLA-4, another T-cell adhesion molecule, and miR-17-92, a micro-RNA cluster, are essential for the homing and activation of therapeutic anti-tumor Type-1 T cells, respectively. This yielded six first-author publications, including publications in Cancer Research and The Journal of Immunology. However, Dr. Sasaki’s interest in clinical research then led him to pursue postgraduate medical training in diagnostic/anatomic pathology at the University of Pittsburgh Medical Center (residency) and the University of Washington Medical Center (renal pathology fellowship). During this time, his detailed histological and immunohistochemical descriptions of various neoplastic and non-neoplastic conditions of urogenital organs, such as adrenal glands and kidneys, nurtured his broader interest in the pathophysiology of the human urogenital organ system.
After completing his clinical training, Dr. Sasaki went back to Japan to pursue his second postdoctoral fellowship in the laboratory of Dr. Mitinori Saitou. There, he studied the development of germ cells in humans and non-human primates using single-cell genomics and stem cell-based approaches. He established robust culture methods to induce human pluripotent stem cells into primordial germ cell (PGC)-like cells, the earliest precursor of both oocytes and sperm, thereby creating a foundation for mechanistic assessment of human germ cells. In parallel, Dr. Sasaki determined that the primate germline originates in the nascent amnion and revealed that germ cell specification pathways of primates and mice have diverged. This discovery finally resolved the mysterious origin of the primate germline and established a framework for the induction of primate germ cells from pluripotent stem cells in vitro.
Human male in vitro gametogenesis
The germ cell lineage ensures transmission of genetic materials to the next generation and, therefore, plays an essential role in the perpetuation of species. Failures in germ cell development result in infertility affecting one in six couples. However, the genetic mechanisms underlying a large fraction of these cases remain elusive due to the lack of tractable models of human germ cell development. Since 2018, the Sasaki lab has focused on establishing new methods to recapitulate human male germ cell development from pluripotent stem cells. First, extending his earlier studies on pluripotent stem cell-derived human PGC-like cells, Dr. Sasaki’s group further induced them to form fetal and adult-stage sperm precursor cells. This platform now allows for mechanistic assessment of human sperm cell development. However, the current protocol only allows differentiation to the spermatocyte stage, and cells do not undergo meiosis to become haploid sperm. The Sasaki lab is currently optimizing this method to allow the successful completion of meiosis, thereby enabling the generation of stem-cell-derived “artificial” sperm cells. This technology will open up a new chapter of reproductive medicine.
Generation of human adrenal gland in dish from pluripotent stem cells
The adrenal cortex is the major endocrine hub for steroid hormone production, and thus regulates a wide array of critical physiologic functions, including immune and stress responses and glucose metabolism. Loss of adrenal function, as occurs in primary adrenal insufficiency, results in a life-threatening disease driven by decreases in cortisol and other critical steroid hormones. To overcome these drawbacks, cell replacement therapy using stem cell-derived adrenal gland has been anticipated. However, because the tissue homeostasis of the adrenal gland is mediated by self-renewal and differentiation of subcortical stem cells, long-term therapeutic effects will require transplantation of both stem cells and surrounding niche cells that support stem cell self-renewal.
Recently, Dr. Sasaki’s team has successfully derived various adrenocortical cell types from human induced pluripotent stem cells using the stepwise and directional induction scheme they invented. Resultant cell types highly resemble normal developmental stages of the human adrenal cortex. Currently, a major goal of the Sasaki lab is to establish self-sustaining and transplantable mature human adrenal cortex organoids that can provide physiologically regulated hormone production for the treatment of primary adrenal insufficiency. As such, their study will not only offer a permanent cure for primary adrenal insufficiency and other adrenal disorders but will also allow for both mechanistic analyses of additional adrenal disorders and for screening therapeutic drugs that regulate adrenal steroidogenesis.