Human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) and recently developed human induced pluripotent stem cells (iPSCs), hold great promise as attractive cell sources for tissue regeneration. Unlike other types of cells, hPSCs can self-renew indefinitely and possess the potential to differentiate into any type of cells in our body. Before hPSCs can be used for therapeutic purposes, methods must be developed to control their differentiation into functional mature cell types. Stem cells reside in a highly complex niche in vivo where they constantly respond to microenvironmental cues including soluble factors, extracellular matrix, adjacent cells and mechanical signals. To fully realize the therapeutic potential of hPSCs, it is critical to understand the mechanisms by which they receive information from microenvironment and how such interactions alter hPSC functions.
While the effect of individual type of microenvironmental cues on stem cell behavior has been studied in great depth, little is known about how the complex interplay of multiple types of microenvironmental cues would influence stem cell behavior. In addition, conventional iterative approach typically requires large amounts of cells and materials, and is slow an inefficient in discovery. To address these limitations, high-throughput screening has emerged as a novel approach to achieve rapid discovery with reduced materials and costs. However, most high-throughput studies on cell-material interactions to date have been performed on two-dimensional environments, while the architecture of the stem cell niche itself is three-dimensional. Recent research have clearly emphasized dimensionality as a critical determinant for regulating cell behavior, and systematic evaluation of stem cell responses to complex 3D signaling environment remains challenging.
Through working at the interface of biology, material science, and engineering, here we propose to develop novel 3D combinatorial systems to understand how microenvironmental signals influences stem cells fate decision in 3D, and to rapidly optimize stem cell niche using high-throughput strategies. Such studies can greatly accelerate the clinical applications of hPSCs by elucidating the mechanisms underlying the control of hPSC differentiation. The outcome of proposed work can also aid in the synthesis of culture microenvironments that emulate stem cell niche in vivo, and would have broad applications in areas such as tissue regeneration and drug delivery.
Statement of Benefit to California:
California is the most populated State in the US and many Californians suffer from diseases and injuries that lead to tissue loss and organ failure. With the rise of average life expectancy in our population, the number of Californians that suffer from devastating diseases will continue to increase. Human pluripotent stem cells (hPSCs) represent a promising candidate as cell sources for tissue repair and regenerative medicine. However, before they can be broadly used for therapeutic purposes, methods must be developed to control their differentiation into functional mature cell types. This proposal aims to elucidate the fundamental mechanisms by which hPSCs respond to the complex microenvironmental cues, and the outcomes of the proposed work will greatly accelerate the clinical translation of hPSCs for treating many Californian patients. Furthermore, the discovery from the proposed work will strengthen the leadership role of California in stem cell research. Our findings could also provide outstanding opportunities to stimulate the growth of biotechnology and pharmaceutical industries within the State as well as creating new job opportunities.