Center for hESC Research
Center for hESC Research
Funding Type:
Shared Labs
Grant Number:
CL1-00502
Investigator:
Funds Committed:
$3,828,751
Stem Cell Use:
Embryonic Stem Cell
Status:
Active
Public Abstract:
The therapeutic use of stem cells in regenerative medicine will require the ability to control stem cell expansion and differentiation into specific tissue types, such as pancreatic ?-cells, heart tissue, bone or specific neuronal lineages. We have taken a chemical approach toward this problem in which large collections of synthetic small molecules are being screened in cell-based assays to identify drug-like molecules that control stem cell processes. Preliminary experiments in our institute have demonstrated that we can identify molecules that control the self-renewal and directed differentiation of murine embryonic stem cells. The characterization of the biological mechanisms of the molecules has also provided new insights into the underlying biology of stem cells. We now propose to extend these studies to hESC lines not eligible for federal funding, for which our research activities have been restricted to date. In addition, such lines may be better suited for specific applications, including the use of small molecules to derive specific cell lineages and investigate ES derived cell-based models of genetic disease. To this end, we would like to establish a human embryonic stem cell core facility. This facility will house the necessary equipment to genetically manipulate and culture hESCs on a large scale for a variety of studies including cell-based screens of small molecule libraries, as well as screens of arrayed genomic cDNA and siRNA libraries. We anticipate that this facility will serve our faculty as well as other labs that would like to collaboratively exploit this chemical approach to the study and manipulation of stem cells.
Statement of Benefit to California:
Historically, small molecules have been more useful than genetic approaches in the treatment of human disease. However, much of our ability to control embryonic stem cell self-renewal and directed differentiation currently involves genetic manipulation of these cells or complex mixtures of protein factors. The demonstration that one can systematically identify, optimize and characterize the mechanism of action of small drug-like molecules that selectively control stem cell biology both in vitro and in vivo will: (1) provide important tools to manipulate stem cells in the lab; (2) provide new insights into the complex biology that regulates stem cell differentiation; and (3) provide an important first step which may ultimately lead to drugs that facilitate the clinical application of stem cells.
Progress Report:
Year 1
The mission of the CIRM Shared Laboratory is to provide researchers with the resources to undertake pilot or long-term projects using stem cell technologies. These resources include basic training (each lab user must take a training course), advanced training and advice, and the use of high quality equipment. In addition to cell culture and cell biology facilities, our center has two unique features: high-throughput molecular profiling (Loring) and high throughput chemical screening (Ding). Each researcher, when qualified, supplies his or her own reagents and supplies, and works under the supervision of the dedicated staff. Cell lines used in the lab are tightly quality controlled.Year 2
The mission of the CIRM Shared Laboratory is to provide researchers with the resources to undertake pilot or long-term projects using stem cell technologies. These resources include basic training (each lab user must take a training course), advanced training and advice, and the use of high quality equipment. In addition to cell culture and cell biology facilities, our center has two unique features: high-throughput molecular profiling (Loring) and high throughput chemical screening (Ding). This shared stem cell lab continues its success and has established itself as a local stem cell hub. Each researcher, when qualified, supplies his or her own reagents and supplies, and works under the supervision of the dedicated staff. In the past year, many researchers from labs locally and nationally continue to use our shared stem cell lab for independent research projects, or participate in the training courses as summarized in details in the report.Year 3
The TSRI Shared Laboratory and Training Center serves the public by providing laboratory tours, public lectures, and special events for public education. New scientific collaborations were established in the past year and there are currently more than 40 active collaborations with local and international researchers. These groups published a remarkable 19 scientific papers last year. The center remains active in Cell Biology, Genomics, and High-Throughput Screening (HTS). Improvements have been to the Chemical Screening Facility which provides a more user friendly space. The equipment is in constant use, and new collaborators are learning how to use HTS and Chemical Screening in their studies. The training courses now include training in induced pluripotent stem cell technology. The courses included training for several Bridges to Stem Cell Research groups, local graduate students, postdoctoral fellows, and a group of researchers from the NIH’s Chemical Screening Center. We plan to maintain our level of involvement with the public, and will participate in events organized by interested lay people.Year 4
The TSRI Shared Laboratory and Training Center serves the public by providing laboratory tours, public lectures, and special events for public education. New scientific collaborations were established in the past year and there are currently more than 45 active collaborations with local and international researchers. These groups published a remarkable number of scientific papers last year. The center remains active in Cell Biology, Genomics, and High-Throughput Screening (HTS). The training courses now include training in induced pluripotent stem cell technology. The courses included training for several Bridges to Stem Cell Research groups, local graduate students, and postdoctoral fellows. We plan to maintain our level of involvement with the public, and will participate in events organized by interested lay people.Publications
- J Invest Dermatol (2013) Melanocytes derived from transgene-free human induced pluripotent stem cells. (PubMed: 23514962)
- Annu Rev Pharmacol Toxicol (2013) Small molecule-based approaches to adult stem cell therapies. (PubMed: 23294307)
- Nat Methods (2012) Conversion of human fibroblasts to angioblast-like progenitor cells. (PubMed: 23202434)
- Nat Cell Biol (2012) The functions of microRNAs in pluripotency and reprogramming. (PubMed: 23131918)
- Nat Biotechnol (2012) Full-length mRNA-Seq from single-cell levels of RNA and individual circulating tumor cells. (PubMed: 22820318)
- EMBO Rep (2012) Equally potent? Does cellular reprogramming justify the abandonment of human embryonic stem cells? (PubMed: 22986548)
- Nature (2012) Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells. (PubMed: 22278060)
- Cell Stem Cell (2012) Recurrent variations in DNA methylation in human pluripotent stem cells and their differentiated derivatives. (PubMed: 22560082)
- Cell Res (2011) Specific lectin biomarkers for isolation of human pluripotent stem cells identified through array-based glycomic analysis. (PubMed: 21894191)
- J Vis Exp (2011) Teratoma Generation in the Testis Capsule. (PubMed: 22158256)
- Nat Methods (2011) A bioinformatic assay for pluripotency in human cells. (PubMed: 21378979)
- Cell Stem Cell (2011) Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture. (PubMed: 21211785)
- Genome Res (2010) Dynamic changes in the human methylome during differentiation. (PubMed: 20133333)
- Cell Stem Cell (2010) Friedreich's ataxia induced pluripotent stem cells model intergenerational GAATTC triplet repeat instability. (PubMed: 21040903)

