Our Researchers in Focus for August are Prof. Günther Eissner, Prof. Owen Smith, Isabel Quiros, and Simeng Li.
Prof. Günther Eissner is a Principal Investigator and Group Leader in Systems Biology Ireland at UCD. Prof. Owen Smith is a Consultant Paediatric Haematologist in the Department of Pediatric Oncology and Haematology at Children’s Health Ireland at Crumlin, and a Principal Investigator/Group Leader in Systems Biology Ireland at UCD. Isabel Quirós and Simeng Li are researchers in Prof. Eissner’s group.
Together, they are working on a collaborative NCRC funded project to identify patients at risk of bone marrow transplant related complications that are specific for the endothelium, the inner lining of the blood vessels – “In-Vitro Monitoring of Endothelial-Specific Immune Reactions Post Transplant”.
Haematopoietic stem cell transplantation is often the only curative option for certain leukaemias (blood cancers caused by the development of abnormal white blood cells) and some hereditary disorders, many of which can be fatal in childhood.
However, this treatment option is not without risks. Transplant related complications are common and can be fatal in some cases. “Children’s Health Ireland at Crumlin is the only Irish hospital that does allogeneic haematopoietic stem cell transplants in children. 14-18 children per year undergo this procedure, but about 30-40% of these children develop transplant-related complications” explained Owen.
A common transplant related complication is damage to endothelium. As endothelial cells play an important role in controlling blood clotting, this damage can drive the formation of blood clots and lead to conditions such as hepatic veno-occlusive disease (clots obstruct blood flow to the liver) and thrombotic microangiopathy (clots obstruct blood flow within small capillaries and arterioles).
Endothelial damage can also be caused by a subclass of white blood cells (T cells) originating from the stem cell donor. Some of them exclusively recognise the recipient’s endothelial cells as foreign and attack them, leading to cell damage and loss of the integrity of the blood vessel wall.
Unfortunately, there is currently no way to determine which patients are at risk of endothelial-specific transplant related complications “Not all transplant recipients will suffer endothelial damage and it has been historically difficult to predict who will be affected” said Günther.
There are medications available that have been shown to reduce endothelial damage. However, as Günther explains “they are often very expensive and their optimal role in prophylaxis [treatment to prevent a disease] during transplant is poorly defined”.
In their project, the research team are trying to develop a lab test that can be used to identify patients who are at risk of endothelial damage and transplant related complications, and those who would benefit most from available medications.
In the test, they will look at how T cells from a stem cell donor specifically interact with the endothelial cells of the stem cell recipient in the lab.
Günther explains “By culturing these donor T cells with patient specific endothelial cell lines generated in the lab, we aim to monitor the risk of endothelial damage for individual donor-recipient pairs. These culture experiments can then be used to identify which patient-donor pairs are most likely to suffer severe endothelial damage”.
A critical step in the development of this test is generating endothelial cells from the stem cell recipient. As it is not possible to directly isolate endothelial cells from the blood vessel wall to a sufficient extent, the team instead will isolate bone marrow mesenchymal stromal cells (MSC, a progenitor cell that can differentiate into various tissue types) and induce them to develop into endothelial-like cells.
Currently, the team are using commercially available and umbilical cord tissue-derived MSC to refine the experimental conditions and have made significant progress. “We could improve the endothelial differentiation of MSC by treating the cells with growth factors and low oxygen (hypoxia) as well as by exposing them to flow/shear stress like it exists in a blood vessel and culturing them in 3D structures” said Isabel and Simeng.
Importantly, they have also been able to show that these differentiated and long living endothelial cells (referred to as endothelial-like MSC or eMSCi) promote an immune reaction when exposed to T cells.
This result shows the potential of their test system. “This important observation ultimately qualifies eMSCi as patient specific target cells for the in vitro monitoring of endothelial cell-specific immune reactions” said Günther.
Once the test conditions are ultimately optimised, the team intend to move towards using samples isolated directly from patients. Ultimately, with this test, the research team hope to be able to classify stem cell transplants based on risk of complications and offer individualised patient specific treatment.
“Low risk patient-donor pairs can be transplanted without the need for endothelial protectant drugs. High risk patient donor pairs can be prescribed a prophylactic drug regimen to protect the endothelium during the peri-transplant period in order to minimise the risk of transplant related mortality” said Günther.
More information on the groups research can be found here:
Eissner Group Website: https://www.ucd.ie/sbi/team/groups/eissnergroup/
Smith Group Website: https://www.ucd.ie/sbi/team/groups/smithgroup/