SDRC member and Stanford Department of Developmental Biology faculty member Dr. Kyle Loh is fascinated by embryonic stem (ES) cell biology and the ability of ES cells to generate all of the cell types within the human body. However, getting ES cells to exclusively turn into a single cell type of therapeutic value, such as an insulin-producing pancreatic beta cell is immensely challenging. “How can we ‘force’ them to turn into a single kind of cell at the expense of other alternatives?”, muses Dr Loh. His group has made huge strides towards addressing this problem by delving deep into understanding the mechanisms underlying ES cell biology. Specifically, his work has systematically identified key molecular pathways controlling specific differentiation routes and has permitted the generation of nearly pure populations of therapeutically useful cell types such as liver cells and bone cells that could be transplanted into mouse models.
Our current understanding of ES cell biology points to a model where multiple factors and signaling pathways essentially keep ES cells in a state of ‘stemness’ or undifferentiation by suppressing differentiation into different cell types. Dr. Loh’s research has led him to challenge this prevailing view. He notes, “This is innately paradoxical to some degree, because a defining property of stem cells is their capacity to differentiate”. Instead, Dr. Loh proposed that the supposed ‘guardians’ of ES cell biology – the individual transcription factors that mark ES cells, may in fact promote differentiation to specific lineages while repressing alternative differentiation pathways. “Thus”, he argues, “co-expression of multiple such competing transcription factors would engender a ‘precarious balance’ whereby multiple downstream lineage options are simultaneously poised but the stem cell does not differentiate into any of them”.
Dr. Loh’s work has provided a road map that allows researchers to nudge ES cells along their differentiation pathway of choice to generate a pure population of therapeutically useful cells. However, he notes that significant challenges remain. “A pure batch of cells is not an organ, and for certain types of cell replacement therapies, it may be necessary to transplant complex constructs comprised of multiple cell types”, he explains.
Another challenge that Dr. Loh is addressing is to ensure that transplanted cells are not rejected by patient immune systems. Immune rejection is a major roadblock for type 1 diabetic patients whose immune systems are programmed to attack not just their own beta cells but also transplanted islet cells. Dr. Loh conducted preclinical animal studies in collaboration with other SDRC members to deplete the host blood system and replace it with healthy donor blood cells through a process known as ‘conditioning’. Dr. Loh anticipates that similar approaches will be instrumental in safely replacing a patient’s immune system and inducing tolerance to transplanted cells.
Dr. Loh’s group is a part of the recently established Juvenile Diabetes Research Foundation (JDRF) Northern California Center of Excellence (COE) to develop cell replacement therapies for type 1 diabetes. The COE comprises a team of investigators from Stanford and the University of California at San Francisco and supported by the SDRC resources and expertise. Speaking about his research partnerships with other SDRC scientists including Drs. Seung Kim and Judith Shizuru to develop regenerative therapies for type 1 diabetes, Dr. Loh says, “It has been great to be part of a well-integrated diabetes research community”.