Modular model of erythropoiesis compartmentalized by Mk TGFβ1. (A) Schematic of proposed compartmentalized model of erythropoiesis. Megakaryocytic TGFβ1 serves as a gatekeeper regulating the feed of committed erythroid progenitors to a maturation module regulated by EPO. EPO-dependent erythroblast survival is controlled by the need for RBC production sensed by oxygen delivery to renal EPO-producing cells. (B) Genetic deletion of TGFβ in Mks, or use of TGFβ ligand trap (1D11), licenses production of unneeded erythroid-committed progenitors. The excess EPs are not supported by homeostatic EPO, undergo apoptosis, and fail to contribute to RBC production. (C) Excess EPs can be rescued to exogenous EPO or increased physiologic demand (eg, supplemental Figure 2).