Synchrony of bone marrow proliferation and maturation as the origin of cyclic haemopoiesis

Abstract

Abstract. Cyclic haemopoiesis in Grey Collie dogs is characterized by stable oscillations in all haemopoietic lineages. It is proposed that in these animals, in contrast to normal animals, the maturation process of haemopoietic (in particular granuloid) cells from the primitive progenitors to the functional cells is characterized by an abnormally strong synchrony. It is conjectured that the marrow maturation time has a very small variance compared with non‐cyclic normal dogs. With a mathematical model of haemopoiesis it is shown that small fluctuations are amplified via regular feedback processes such that stable granuloid oscillations are established. Erythroid oscillations are induced indirectly by granuloid feedback to the stem cell pool. The model calculations further show that the synchrony hypothesis of bone marrow maturation can quantitatively explain the following experimental results: (1) the maintenance of stable cycles of granuloid and erythroid bone marrow and blood cells with a period of approximately 14 d; (2) the disappearance of granuloid and erythroid cycles during the administration of the colony stimulating factor rhG‐CSF; (3) the reappearance of oscillations when the administration of CSF is discontinued; (4) the cessation of cycles during endotoxin application; and (5) the persistence of cycles during erythroid manipulations (bleeding anaemia, hypoxia, hypertransfusion). We therefore conclude that cyclic haemopoiesis is not caused by a defect in the regulatory control system but by an unusual maturation process.

Modeling Complex Neutrophil Dynamics in the Grey Collie

“…& van den Driessche, 1979;King-Smith & Morley, 1970;MacDonald, 1978;Morley et al, 1969;Morley & Stohlman, 1970;Morley, 1970Morley, , 1979Reeve, 1973;Schmitz, 1988;Schmitz et al, 1993Schmitz et al, , 1994Schmitz et al, , 1995Schmitz et al, , 1990Shvitra et al, 1983;von Schulthess & Mazer, 1982;Wichmann et al, 1988). However, recent modeling (Hearn et al, 1998) has shown that a destabilization of this feedback pathway cannot account for the onset of oscillations seen in CN, and concluded that CN was probably not solely due to an instability in the peripheral feedback loop.…”

Blood Cell Dynamics: Half of a Century of Modelling

“…Two pathologies rose the attention of these two groups: chronic myelogenous leukemia in its periodic form [133] and [283], [192], both in the late 1990's, and cyclic neutropenia, starting in the middle of the 1990's too for Loeffler [265] and late 1990's for Mackey [156]. Other general cyclic hematopoietic diseases were studied [264], some with chemotherapy modeling attempts [270], [163] or treatments [142] and other hematotoxic products [260]. Few works were focused on erythropoiesis, besides some theoretical approaches from Bélair et al [54], [202], [254], [256] and some attempts to fit experimental data for anemia [189], or erythropoietin (EPO) effect [98], [101].…”

A computational model of human granulopoiesis to simulate the hematotoxic effects of multicycle polychemotherapy

“…The GM-CSF feedback loop has been described in detail previously. 24,26,27 The efferent part of the G-CSF loop controls the amplification in PGP, the transit time in MGP, and the rate of cells emerging from bone marrow to the peripheral blood. The afferent part of the loop controls the present serum concentration of G-CSF.…”

“…[23][24][25][26] Figure 1 gives an overview of the model structure. The model considers human granulopoiesis as a set of compartments, each representing the population size (ie, cell number) of a distinct hematopoietic cell stage.…”

“…Previous work of our group has shown that a large number of experimentally induced or disease-related hematopoietic disturbances in the mouse, dog, or human being can be described by this model approach. [24][25][26][27][32][33][34][35] …”