Important Discovery for the Transplantation of Hematopoietic Stem Cells
Surface Molecule Supporting Hematopoietic Recovery after Transplantation of Blood Stem Cells Identified
Transplantation of blood stem cells (haematopoietic stem cell transplantation) is an important treatment option for patients with haematopoietic disorders. This method is also applied in hematopoietic stem cell-directed gene therapy. Researchers from the Paul-Ehrlich-Institut (PEI), Federal Institute for Vaccines and Biomedicines identified the endothelial protein-C receptor (EPCR) on hematopoietic stem cells to improve stem cell transplantation. These research results are reported in the journal Blood in its online version of 25.01.2019.
Blood cells are constantly renewed – platelets for instance have a life time of a few days and red blood cells between one and three months. These blood cells derive from blood stem cells (haematopoietic stem cells) residing in the bone marrow and differentiating into all different blood cell types. They can self-renew and switch to quiescence to protect themselves against exhaustion caused by frequent cell division. When the process of differentiation, self-renewal, and quiescence is disturbed, blood cell disorders can develop. This can be the case, for instance, in blood cell diseases such as leukemia or aplastic anaemia, which, in the event of loss of blood stem cells, lead to a blood cell deficiency. A possible therapy option by aplastic anaemia is the transplantation of blood stem cells from suitable donors (haematopoietic stem cell transplantation).
Surface Protein Supports Hematopoietic Recovery
Which factors will affect the success of this treatment? This question was asked by Professor Ute Modlich, head of the research group "Gene Modification in Stem Cells" at the PEI and her co-workers. For this purpose, she used a mouse model of aplastic anaemia. In the mice, the central signal pathway of the cytokine thrombopoietin (Thpo) is blocked by deleting its receptor Mpl (myeloproliferative leukaemia virus oncogene, Mpl-deficient mice).
These mice mimic the phenotype of patients with aplastic anaemia caused by inactivating mutations in the same pathway. Blood stem cells of Mpl-deficient mice engraft and expand only very poorly after transplantation.
The Mpl receptor activates various pathways. Which pathway is important for the stem cell preserving function of Thpo/Mpl? To find the answer, researchers expressed potential Thpo-target genes with lentiviral vectors in Mpl-deficient blood stem cells. These cells were transplanted into Mpl-deficient recipient mice and hematopoietic recovery evaluated.
Of the five candidate genes studied, the surface protein EPCR (endothelial protein-C receptor) proved to be an important player: Was this surface protein present on blood stem cells, they expanded and could also transition into quiescence. In mice which received these modified stem cells (Epcr+Mpl-deficient), a large number of donor cells could be detected in the bone marrow appropriately fast. In further experiments, the PEI researchers proved that Epcr marked the engrafting blood stem cells also in normal haematopoiesis and that they expanded well after stem cell transplantation.
Epcr is known as co-receptor for the protease-activated receptor (PAR1) on endothelial cells. This receptor can be activated by its ligand, activated protein C (aPC). Professor Modlich explained the significance of these research results by stating “We have identified a target structure which we may be able to use to support blood stem cell transplantations. This could be useful in particular in gene therapy where blood stem cells are genetically modified in culture before these cells are transplanted.”
Saskia Kohlscheen, Franziska Schenk, Marcel G.E. Rommel, Katharina Cullmann and Ute Modlich: Endothelial protein C receptor supports hematopoietic stem cell engraftment and expansion in Mpl-deficient mice, Blood (2019); DOI: [10.1182/blood-2018-03-837344 ].