Mathematical modelling of megakaryopoiesis in Mpl-deficient and continuously thrombopoietin-stimulated mice points to an unknown control mechanism

Thrombopoietin (TPO) is the ligand of the Mpl receptor and the key regulator of megakaryopoiesis and platelet production. A loss or gain of the TPO-receptor function affects haematopoiesis and results in severe diseases in humans. Appropriate mouse strains are available to mimic both myeloproliferative neoplasm (MPN) and congenital amegakaryocytic thrombocytopenia (CAMT) resulting from TPO overexpression or knockout of TPO receptor Mpl on megakaryocytes and platelets, respectively. However, at a quantitative level it is not understood, how the known regulations can establish the impaired but stable disease phenotypes. Starting out from an established mathematical model for megakaryopoiesis, we aim to adapt it to both the healthy situation and to distinct diseased phenotypes mimicking MPN. We thereby identify, that some of the model parameters are invariant with respect to the mouse strain while others have to be estimated in a strain-dependent manner. A systematic process of parameter identification provides strong evidence that the well-known excess production of megakaryocytes and early progenitors in MPN is either directly contingent on Mpl expression of platelets and megakaryocytes or, alternatively, that the knockout of Mpl is not as precisely restricted to megakaryocytes and platelets but may also effect their progenitors. In conclusion, our analysis hints towards an opaque control mechanism rendering megakaryopoiesis at a yet unknown level, and awaiting further experimental evaluation.