Cytokine-free rapid red cell regeneration.

A novel mutation in the P2Y 12 receptor and a function-reducing polymorphism in protease-activated receptor 1 in a patient with chronic bleeding. In this issue of Blood, Belay et al present evidence of human bipotent erythroid-megakaryocyte precursor cells that can bypass the burst-forming unit-erythroid (BFU-E) and colony-forming unit-erythroid (CFU-E) stages and directly and rapidly differentiate into either erythrocytes or megakaryocytes. 1 T he properties of the cells they describe resemble those of cells previously observed during stress erythropoiesis in mice, also initially reported in Blood, 2,3 suggesting the existence of a novel cellular response to erythropoietic stress in both mice and humans. The studies reported by Belay et al are an extension of their work pursued for many years on expansion of hematopoietic stem progenitor cells (HSPCs) ex vivo using a novel engineered artificial cell growth switch (CGS) receptor consisting of the Mpl intracellular signaling domain fused to a dimerizable receptor for a small drug molecule referred to as a chemical inducer of dimerization (CID). Previous work using the CGS system showed that cell expansion was limited to primitive erythroid T and B cells, megakaryocytes, and platelets, with minimal effects on primitive HSPCs. Belay et al hypothesize that the lack of expansion of primitive HSPCs is due to low levels of CGS signaling from the CGS receptor, and therefore attempt to improve CGS signaling by introducing point mutations at locations within the Mpl signaling domain involved in degradation of the human Mpl receptor. These engineered hyperactive Mpl constructs increase the sensitivity and responsiveness to an exogenous CID when introduced into human adult or cord blood CD34 1 cells and significantly improve the expansion of CD34 1 cells and maintenance of colony-forming cells. No evidence is presented regarding expansion of the most primitive hematopoietic stem cells. Through careful and detailed efforts to characterize the CGS-expanded cell populations, Belay et al identified a novel cell type. 1 A population of CD235 1 /CD41 1 cells was expanded .70-fold and constituted up to 13% of cultured CGS-expanded cells. This CD235 1 /CD41 1 cell population contained few colony-forming cells but could rapidly differentiate (within 48 hours) into erythrocytes and megakaryocytes. Differentiation was not dependent on stem cell factor or associated with increased cell numbers. Low numbers of these CD235 1 /CD41 1 bipotent precursors were also observed in unexpanded cord blood cell populations. The properties of these cells closely resemble those of a …