Unbeknownst to many, stem cells have been used to treat patients for over four decades. Although not known at the time, bone marrow transplants – which are used commonly to treat blood disorders and cancers – are nothing more than transplants of hematopoetic stem cells. As a physician-scientist, this means to me that stem cell-based therapies for other human disorders are not questions of if, but when.
My goal is to help us turn ‘when’ into ‘now’, by investigating mouse neural stem cell (NSC) findings with important clinical potential, determining the strength of their potential, then turning them into clinical realities by using human embryonic stem cells (hESCs). As a neuropathologist who specializes in the problems of infants and children, mice and their NSCs have helped us greatly to understand how and why brain development sometimes goes wrong. Now, with the advent of hESC culture systems, we have cells that provide better models of human brain disorders and can be used to treat them.
In our first Aim, we will try to make choroid plexus epithelial (CPE) cells in a dish. Although not famous, CPE cells are extremely important for brain health and have tremendous clinical potential. The inability to grow CPE cells in culture has been a roadblock, but we have solved at least part of this puzzle. In this Aim, we use mice to figure out the factors needed to make CPE, then apply this knowledge to ESC cultures. We also look for adult CPE cells that can grow. Either avenue, if successful, would open up a number of direct applications for CPE cells in drug testing and clinical therapies.
In the second Aim, we try to make neural stem cells that can ‘sort’ themselves. Sorting is the process of purifying desired cells away from unwanted ones, a general issue for regenerative medicine. If given the opportunity, some stem cells may be smart enough to sort themselves, and we have identified a factor that may provide this opportunity. In this Aim, we use mice to understand better what this factor does and use this factor in ESC cultures. If successful, this would provide a simple way to purify one type of stem cell for clinical applications, and the rationale to use self-sorting as a general approach.
The third Aim also deals with the problem of sorting. We took an approach shown by others to distinguish highly similar cell types, but not stem cells. Remarkably, this approach not only detects subtle differences between stem cells, but apparently informs us about the kinds of cells that each stem cell can make. To our knowledge, this is a very unique capability. In this Aim, we use this bioengineering tool on a wide range of cells to see how well this principle holds up and to apply this principle to sort cells. If successful, this would be a brand-new way, which could be used alone or along with existing methods, to get the best cells for all sorts of clinical applications.
Statement of Benefit to California:
Our goal is to use human embryonic stem cells (hESCs) to help us understand human brain development and its disorders better and to make cells to treat these disorders. The project has three Aims: 1) to make choroid plexus epithelial cells, which have significant and largely untapped therapeutic potential, 2) to allow stem cells to sort themselves, which could be a simple general approach for purifying cells, and 3) to enrich for stem cells with specific properties using a bioengineering technology with unique capabilities. If successful in generating and purifying novel cell types with clinical utility, this project should have immediate and direct benefits to the State of California and its citizens, including pharmaceutical companies, basic scientists, clinicians, and patients. In addition, as a culture model for human brain development, the hESC studies should provide insights into developmental brain disorders that could lead to improved diagnostics for patients and their families.