Novel use of a family of microRNAs to promote the de-differentiation of somatic cells to induce pluripotent stem cells (iPS cells) for use as therapeutic agents or research tools.

This invention describes a robust method to generate functional human beta cell equivalents from pluripotent stem cells in vitro for wide applications in basic research, drug and toxicology screens and as a diabetes cell therapy.

Investigators at UCSF have developed a novel robust protocol for programing human embryonic stem cells (hESCs) into thymic epithelial progenitors (TEPs) in vitro.

A cornerstone of regenerative medicine is the study and use of pluripotent stem cells for the purpose of wound healing, tissue repair, and organ transplantation. Existing forms of pluripotent cells include embryonic stem (ES) cells and induced pluripotent stem (iPS) cells. The ethical concerns and limited availability associated with ES cells, and the difficulties in generating large quantities of iPS cells underscore the necessity of finding additional sources of pluripotent cells.

Stem cell based musculoskeletal tissue-engineering presents the unique opportunity to repair or replace dysfunctional cells in degenerating tissue. In this context, one goal of tissue engineering is to propagate stem cells that can then be reintroduced into the degenerating tissue to repair or replace dysfunctional cells, restore the physical and biochemical properties of the tissue, and re-establish normal function. In particular, mesenchymal stem cells (MSC) are useful in the treatment of musculoskeletal degenerative conditions such as degenerative disc disease and osteoarthritis.  MSCs are abundant, relatively easy to isolate, and can differentiate into a variety of cell types. However, the ischemic and inflammatory environment characteristic of injured tissues proves hostile for the direct introduction of MSCs, which often do not survive in this setting. While growth factors are commonly used to pre-differentiate MSCs into chondrocytes prior to their use, this can cause terminal differentiation and cell hypertrophy that leads to inferior extracellular matrix material properties. Instead, pellet culture systems are better suited for tissue engineering because they can mimic certain embryonic microenvironments that stimulate stable cell differentiation and better support the regenerative process.    

Over 5 million Americans currently suffer with congestive heart failure and despite aggressive medical therapies targeted to treat this disease; the outlook for these patients remains grim, with estimated mortalities of 33% and 50% at 1 and 5 years, respectively. Congestive heart failure (CHF) remains a significant unmet need in the global medical community. A treatment option for CHF by cellular transplantation of stem cells is a developing research area. This approach has been studied using fetal cardiomyocytes, adult skeletal muscle cells, autologous bone marrow-derived mesenchymal stem cells, cardiac progenitor (CP) cells, and cardiomyocytes derived from embryonic stem cells. However, current studies have yielded modest results in reducing infarct size and scar tissue. Furthermore, the necrotic/apoptotic loss of the vast majority of donor cells within days after transplantation is a major drawback. 

The Dact2 protein may play an important role in oncogenesis, metastasis, wound healing and stem cell biology.  Molecular signaling pathways potentially involving Dact2 include the Wnt/b-catenin pathway, the Wnt/PCP non-b-catenin-dependent pathway, regulation of small GTPases of the Rho family, and pathways involving the Dishevelled signal transduction molecule, such as p120-catenin signaling.  There is evidence that Dact2 also regulates the TGF-b pathway.  In vitro and in vivo knockdown models would be very useful for studying Dact2 function in disease, but have not been reported to date.

Research into modulating immune function through immunostimulatory T cells has been hampered by the lack of identification of the molecular markers on such cells. UCSF investigators have identified a novel endogenous human T cell population that can significantly enhance the proliferative capacity of a T cell response. In contrast to T cells that can be induced to suppress a proliferative response, these are a naturally occurring, functionally mature T-cell subpopulation that induce the proliferation of a T cell.