Generation of Blood Vessel Organoids from Human Pluripotent Stem Cells
This week we profile a recent publication in Nature Protocols from Dr. Reiner Wimmer (pictured, right)
in the laboratory of Dr. Josef Penninger (left) at UBC and the Austrian Academy of Sciences.
Can you provide a brief overview of your lab’s current research focus?
The overall goal of our lab is to develop new and effective treatments for diseases by uncovering the fundamental biological principles underlying development and disease. Many diseases often cannot be mapped to only one cell type, one single factor or one anatomical region. For instance, we now know that Parkinson’s disease is not simply a neurological condition, but rather involves many additional players such as our immune system, blood system and even the microflora in our gut. Similarly, our lab has shown for example how one factor, RANKL, is important in a variety of biological processes and diseases from bone metabolism, immune functioning and thermoregulation, to breast and lung cancers. As a result, our research focuses on many different aspects of human disease. Some of the current projects include the study of the immune system in cancer and Parkinson’s, the glycoproteomic landscape of cancers as well as diabetes mediated blood vessel damages, using our recently engineered human blood vessel organoids.
What is the significance of the findings in this publication?
We previously reported the development of self-organizing blood vessel organoids from human pluripotent stem cells. These blood vessel organoids recapitulate the architecture, molecular signatures and function of human blood vessels. We could use the human blood vessel organoids to model various hallmarks of diabetic vascular complications, the major cause of blindness, kidney failure, heart attacks, stroke and amputation of lower limbs. With drug screening approaches and in vivo transplantations of organoids we finally identified a deregulated Notch3-Dll4 signaling axis that triggers aspects basal membrane thickening in diabetic vasculopathy, including in diabetic patients. Diabetes affects 420 million people, with more than 500 million people being pre-diabetic, and to our knowledge no drug exists that can effectively prevent or treat such diabetes blood vessel changes.
In our new published work, we describe in a detailed step-by-step manner the generation of blood vessel organoids from pluripotent stem cells. We improved the previous version of our protocol which is now also faster (16 days in total). The protocol also includes a detailed manual for the analysis of the in vitro grown and transplanted organoids. This will allow all researchers to setup vascular organoid cultures with standard cell culture lab equipment and implement this into their research of diabetes, stroke, ischemia or any other disease affecting the vasculature.
What are the next steps for this research?
We strongly believe that our human blood vessel organoids have an enormous potential and can be used to study a vast variety of vascular diseases or could be utilized for regenerative medicine purposes. In the future we will use blood vessel organoids to study various genetic vascular diseases using patient-specific induced pluripotent stem cells (iPSCs) with the goal to develop novel therapies for those patients. We also plan to translate our organoids as a therapy for non-healing wounds, to support healing in surgeries of weakly vascularized organoids such as bone or cartilage, or to combine them with islet organoids or skin sheets to improve the islet or transplantation. Our model can now be also used to test and improve drugs in a true human vascular setting.