Grant Award Details
Engineering microscale tissue constructs from human pluripotent stem cells
- Development of 3D microscale tissue constructs from human pluripotent cells to generate in vitro models of physiologically mature cardiomyocytes and neuronal tissue.
Human Stem Cell Use:
Embryonic Stem Cell
This past year we successfully transitioned our laboratory to the Gladstone Institutes and have significantly increased our work with differentiation and engineering of 3D tissue constructs from human pluripotent stem cells (PSCs). Our primary efforts are focused on the development of 3D models of heart muscle and spinal cord tissues from human PSCs that can be used as novel model systems to study early human developmental events and serve as substrates for advanced pharmaceutical screening platforms. We are creating small (microscale) 3D tissue constructs from primitive human PSC differentiated cells and examining the effects of 3D culture along with inclusion of supporting cells, like fibroblasts and glial cells, on heart muscle and spinal cord neuron maturation, respectively. We are also examining the effects of developmentally relevant hormone treatments of our 3D constructs in an effort to better understand hormonal effects on tissue development and primitive cell maturation.
The objective of this proposal is to develop cardiac and neural 3D microtissues from human pluripotent stem cell (PSC) sources that can be used to model human development and disease as well as potentially be used directly for regenerative medicine therapies. During the past year we have made significant progress in creating 3D cardiac microtissues from heart muscle and supporting cells derived from PSCs and/or human tissue. We have begun to characterize the effects of combining the different cell types in a controlled manner in order to understand how the different cells influence each other and also affect tissue function. We anticipate that these investigations will lead to better models of engineered cardiac tissue that more accurately reflect properties of real heart tissue. In order to develop new 3D models of neural tissue, particularly spinal cord, we have successfully differentiated multiple neuronal cell types, including a new excitatory spinal interneuron (V2a) that has not previously been reported from human PSCs. We are now preparing to combine different types of spinal neurons using our 3D technologies in an attempt to create a model of human spinal cord. Lastly, we are using engineered PSC lines to examine how cells self-organize to create complex structures during tissue development. These latter studies we anticipate could lead to novel ways to pattern the multicellular organization of 3D tissues derived from PSCs.
<p style="margin-top:9.0pt;line-height:normal;">As a result of this CIRM award, we have been able to develop 3D human models of cardiac and neural tissues derived from pluripotent stem cell sources. These systems are currently being used to study mechanisms of human tissue biology in culture that can not be done using existing animal models or other alternative systems. Furthermore, these stem cell-derived tissues are now being used to study the impacts of genome editing outcomes, which will allow safety and efficacy testing in the future</p>
Grant Application Details
- Engineering microscale tissue constructs from human pluripotent stem cells
Tissues derived from stem cells can serve multiple purposes to enhance biomedical therapies. Human tissues engineered from stem cells hold tremendous potential to serve as better substrates for the discovery and development of new drugs, accurately model development or disease progression, and one day ultimately be used directly to repair, restore and replace traumatically injured and chronically degenerative organs. However, realizing the full potential of stem cells for regenerative medicine applications will require the ability to produce constructs that not only resemble the structure of real tissues, but also recapitulate appropriate physiological functions. In addition, engineered tissues should behave similarly regardless of the varying source of cells, thus requiring robust, reproducible and scalable methods of biofabrication that can be achieved using a holistic systems engineering approach. The primary objective of this research proposal is to create models of cardiac and neural human tissues from stem cells that can be used for various purposes to improve the quality of human health.
Statement of Benefit to California:
California has become internationally renowned as home to the world's most cutting-edge stem cell biology and a global leader of clinical translation and commercialization activities for stem cell technologies and therapies. California has become the focus of worldwide attention due in large part to the significant investment made by the citizens of the state to prioritize innovative stem cell research as a critical step in advancing future biomedical therapies that can significantly improve the quality of life for countless numbers of people suffering from traumatic injuries, congenital disorders and chronic degenerative diseases. At this stage, additional investment in integration of novel tissue engineering principles with fundamental stem cell research will enable the development of novel human tissue constructs that can be used to further the translational use of stem cell-derived tissues for regenerative medicine applications. This proposal would enable the recruitment of a leading biomedical engineer with significant tissue engineering experience to collaborate with leading cardiovascular and neural investigators. The expected result will be development of new approaches to engineer transplantable tissues from pluripotent stem cell sources leading to new regenerative therapies as well as an enhanced understanding of mechanisms regulating human tissue development.
Source URL: https://www.cirm.ca.gov/our-progress/awards/engineering-microscale-tissue-constructs-human-pluripotent-stem-cells