G.T. Matioli

Stochastic development of stem cells

The stochastic model of Till, McCulloch & Siminovitch (1964) for the development of a colony from a stem cell is generalized, and expressions are derived for the moments of any order of the stem cell distribution, especially mean and standard deviation. Furthermore, expressions for the probability for the extinction of a colony are given. The model is applied principally to the development of erythroblastic colonies. Values of the stem cell percentage and total cell number, as calculated from the model, and experimentally observed in developing colonies, are in satisfactory agreement, provided the chain of differentiating erythroblasts is expanded.

Electrophoresis of hemoglobin in single erythrocytes.

A technique for electrophoretic analysis of the hemoglobin mixtures from single erythrocytes has been developed. Hemoglobin mixtures were separated into their constituents, A2, A, C, S, and J, at least qualitatively.

Denaturation of ferritin and its relationship with hemosiderin.

The fate of the ferritin molecules in vitro after degration with oxidizing agents and tryptic digestion has been determined using chemical, serological, and electron optical techniques. Oxidizing agents used were acetylphenylhydrazine, hydrogen peroxide, and molecular oxygen. The denaturation products of oxidized ferritin are compared with hemosiderin with respect to physicochemical, immunological, and ultrastructural characteristics. The conclusion is drawn that hemosiderin in vivo is a denaturation product of ferritin. The possible mechanism of the biosynthesis of hemosiderin in living tissue is discussed taking into account the above conclusion.

On monosegmental sister chromatid exchanges (SCE)

Considerations are given to special features of the nuclear envelope that might occasion segmental exchange between sister chromatids. The underlying dynamics may lead to illegal apposition of originally distant sequences and/or to modulations in the topologic orientation of genes on chromatid segments involved in such exchanges.

Differentiation trajectories in normal and malignant cells

We discuss a model for the organization of differentiation paths within the vector spaces of the cell genome. It is conjectured that the nuclear vesicle apparatus participates in the coordination of genes along nuclear trajectories directing cell commitment to terminal maturation. In this scenario, nuclear (onco)genes are interpreted as regulators of transcriptional exchanges among spatially correlated genes. The paper digresses on events leading to anachronistic acquisition of immortal growth by normally dependent cells as well as on the time and path dependent incidence of cancer, in vivo. Albeit the mathematico-physical foundations have been largely ignored, the basic ideas were derived from order-disorder transitions in chaotic systems whose dynamics are not pervasively random. The paper ends with a brief note on tumor heterogeneity, seen as a logistic phenomenon complementing the interpretation offered by (1).

Glycoprotein Biosynthesis in Human Reticulocytes: A Lesion in Thalassemia

The rate of incorporation of glucosamine into the glycoprotein of reticulocyte stroma is greatly increased in thalassemia. This increase suggests a major enzymic disorder in the buildup of cellular membrane and reconciles the accumulation of material showing a positive reaction with periodic acid Schiff reagent with the clinical picture of oligocythemia and microcytosis.

Midsegmental exchanges between sister chromatids

The model for SCE, proposed by (1), is adapted to the exchange of one or more segments located midway along the chromatid axis. In spite of conflicts in the handedness of these midsegments, the model accounts for the undistorted stacking of both sister chromatids.

Scaling concepts in cellular and subcellular dynamics

After developing a map for certain states typical of hemopoietic stem cells (SCs), we identify a number of parameters (e.g. fractal dimensions, oscillatory behavior in a multistable landscape, etc.) that scale down to subcellular structures such as interphase genome, chromatids, chromatin entanglements and DNA segmental motions. A curious aspect is the continuous reappearance of recursive processes even at very small biologic scales. These iterations are relevant not only for the normal behavior of (hemopoietic) cells but also for amplifying hidden genomic singularities above some critical threshold. When that happens, there are sudden quali-quantitative and often clonal changes in the cell behavior. As illustrated by specific leukemic cases, many paradoxes of malignant growth seem best explained by the peculiar sensitivity to initial condition of (hemopoietic) cells. Interpreted as chaotic oscillators, these cells display a spectrum of disorders that, in spite of appearing as random, are in fact triggered by amplification of subtle preconditions with statistico-deterministic outcomes, that are predictable within certain time limits.

Hemopoietic stem cell growth and microdiffusion

Abstract Extensive experiments carried out to study the kinetics of stem cell growth in the spleen of irradiated mice are reported here and the methods used are elaborated. The temporal and spatial features of the growth of the hypernetted, interacting system of stem cell chains in the spleen may be understood on the basis of a random distribution of source cells and of a microdiffusing stimulus for stem cell renewal along the cell chains. To test the validity of these assumptions, the growth kinetics are studied after administering various doses of colchicine to stem cells during different stages of growth. The behavior of the various phases of the recovery curves lends support to the theory of microdiffusion. Using the number of stem cells at saturation, the diffusion coefficient of the stimulus for renewal is approximately 10-7 cm2 sec-1.

On the myeloblast as initiator of certain human leukemias

We reconsider the proposal that a stem cell (SC) is the initiator of clonal (human) leukemias. Using chronic myeloid leukemia (CML) as an example, we discuss some conceptual and experimental inconsistencies of the above conjecture. As an alternative, it is proposed that CML is initiated by an immature myeloblast. The main idea is that CML results from certain growth-related accidents encountered along the myeloid differentiation path. Retrodifferentiation of (semi) autonomous myeloblasts back to the SC state seems the principle cause for the distribution of clonal markers across all hemopoietic lineages, including those that are not involved in the leukemic process.