466 CORRADO BAG LION 1 



D. MODELS OF RED CELL DU FERENTLVriON AND SYNTHESIS OF Hb-F 



Red cells are formed through a process of differentiation from nucle- 

 ated precursors. A continuous series of morphologically well-defined 

 intermediate stages of differentiation between undifferentiated precursors 

 (stem cells) and red cells has long been recognized (see Wintrobe, 1962). 

 Several models of stem cell differentiation have been proposed recently 

 to explain the kinetics of red cell production and its modifications in 

 pathological conditions (Alpen and Cranmore, 1959; Stohlman, 1959; 

 Lajtha and Oliver, 1960). Every model of red cell proliferation indicates 

 the necessity for the perpetuation of the primitive stem cells in the 

 absence of differentiation. The stem cells appear to be morphologically 

 and biochemically undifferentiated; they act as a reservoir of potential 

 blood cells. Only a small proportion of stem cells per unit of time under- 

 goes differentiation normally, while replication of undifferentiated stem 

 cells provides the somatic continuity of the cell line. 



Barnes et al. (1959) have transplanted 10^ nucleated cells from the 

 spleen of an infant T6+ mouse to an irradiated CBA mouse; from the 

 bone marrow of the latter the same number of cells were serially trans- 

 planted into irradiated CBA mice, succeeding each time in populating 

 the bone marrow of the CBA mice with cytologically distinguishable T6+ 

 cells. This experiment provides direct experimental evidence of the 

 unlimited proliferative ability of the stem cells. 



It has been proposed by Alpen and Cranmore (1959) that the normal 

 supply of red cells is, in large part, provided by the division of already 

 differentiated eiythroid precursors, called erythroblasts or pronormo- 

 blasts. Since the synthesis and the accumulation of hemoglobin initiates 

 soon after the stem cells differentiate into erythroid precursors, these 

 cells can be specifically labeled by means of the radioactive isotope 

 Fe^^. The erythroblast is the earliest cell type that incorporates meas- 

 urable amounts of Fe^^ ; the label incorporated can be estimated by auto- 

 radiographic techniques in which the grains produced by single cells are 

 counted; division of the cells causes halving of the grain count. Alpen 

 and Cranmore (1959) have observed that some of the erythroblasts 

 divide without differentiating further and suggested that the erythro- 

 blasts may divide into a nearly equal number of cells which will dif- 

 ferentiate further, and of cells which do not differentiate but provide the 

 continuity of the cell line. 



In animals made anemic by bleeding, a large number of stem cells 

 differentiate rapidly into erythroblasts (Lajtha and Oliver, 1960) to 

 compensate for the increased demand in red cell output. Whereas 24 

 hours after Fe^^ injection 100% of the erythroblasts are labeled in 



