Population Of Pluripotential Stem Cells Research Articles

A Model of Oscillatory Blood Cell Counts in Chronic Myelogenous Leukaemia

In certain blood diseases, oscillations are found in blood cell counts. Particularly, such oscillations are sometimes found in chronic myelogenous leukaemia, and then occur in all the derived blood cell types: red blood cells, white blood cells, and platelets. It has been suggested that such oscillations arise because of an instability in the pluri-potential stem cell population, associated with its regulatory control system. In this paper, we consider how such oscillations can arise in a model of competition between normal (S) and genetically altered abnormal (A) stem cells, as the latter population grows at the expense of the former. We use an analytic model of long period oscillations to describe regions of oscillatory behaviour in the S-A phase plane, and give parametric criteria to describe when such oscillations will occur. We also describe a mechanism which can explain dynamically how the transformation from chronic phase to acute phase and blast crisis can occur.

Pluripotent stem cells identified in multiple murine tissues.

Pluripotential stem cells (PSCs) have been recently described in many tissues including skeletal muscle, brain, and bone marrow. However, the true nature of these cells is still unclear, and their precise definition has yet to be determined. We hypothesized that a common, rare population of PSCs with a broad tissue differentiation potential can be identified in multiple murine tissues and that these cells are capable of transdifferentiation into cells of different primordial germ layer origins in response to diverse microenvironmental cues. To examine this hypothesis, we isolated phenotypically defined cells from murine skeletal muscle and cultured these cells under different conditions tailored to promote differentiation into several cell types including myocytes. We report here that in conditions permissive for hematopoietic differentiation, muscle-derived CD45(-)Sca-1(+)c-kit(-) cells differentiated into cells expressing hematopoietic-specific mRNA; while in conditions promoting myogenic, neuronal, and adipocytic differentiation, cells morphologically typical of these cell types expressing tissue-specific markers were identified 9-14 days in culture. When CD45(-)Sca-1(+)c-kit(-) cells from muscle or bone marrow were transplanted intracerebellarly into Purkinje cell degenerative (pcd) mice, the behavior of these mice improved 28 days after transplantation relative to mice injected with vehicle alone, suggesting that these cells contributed to the appearance of functional neuronal cells that may have improved the ataxic condition characteristic of these mice. Phenotypic analysis of single cell suspensions prepared from brain, blood, and intestinal epithelium revealed the presence of CD45(-)Sca-1(+)c-kit(-) cells in varying degrees. These studies suggest that a phenotypically common, multipotent cell can be identified in different tissues and that this cell may represent a universal pluripotent stem cell residing at different levels in multiple murine tissues.

LARGE SCALE-INVARIANT FLUCTUATIONS IN NORMAL BLOOD CELL COUNTS: A SIGN OF CRITICALITY?

All types of blood cells are formed by differentiation from a small self-maintaining population of pluri-potential stem cells in the bone marrow. Despite abundant information on the molecular aspects of division, differentiation, commitment and maturation of these cells, comparatively little is known about the dynamics of the system as a whole, and how it works to maintain this complex "ecology" in the observed normal ranges throughout life. Here we report unexpected large, scale-free, fluctuations detected from the first long-term analysis of the day-to-day variability of a healthy animal's blood cell counts measured over 1 000 days. This scale-invariance cannot be accounted for by current theoretical models, and resembles some of the scenarios described for self-organized criticality.

Cyclical Neutropenia and the Peripheral Control of White Blood Cell Production

Cyclical neutropenia (CN) is an interesting dynamic hematological disease in which the neutrophils spontaneously oscillate from approximately normal levels to near zero with a period between 19 and 21 days. In the only known animal model for this disorder, the grey collie, the disease's single apparent difference from human CN is the smaller period of 11–15 days. CN can be treated using the cytokine G-CSF which decreases the period (to about 14 days in humans), increases the mean value, and elevates the amplitude of the oscillations. After reviewing the clinical and laboratory data on this disease, we examine the proposition that CN is due to a loss of stability in the peripheral negative feedback control of neutrophil production. This is accomplished by the development of a physiologically realist mathematical model for the system. We conclude that there is no consistent way in which such a destabilization can give rise to either the clinical or laboratory characteristics of CN. Rather it seems more likely that the oscillations of CN are generated within the pluripotential stem cell population.

Mouse embryo stem cells: their identification, propagation and manipulation

The early mouse embryo contains a transient population of pluripotential stem cells which are responsible for generating both the foetal primordia and extraembryonic membranes. The characterisation of murine embryo stem cells and their isolation and propagation in culture provides the first instance in which pure populations of normal stem cells are directly accessible to the researcher. This marks a considerable advance in stem cell biology which may pave the way to the dissection of general stem cell control mechanisms and the identification of key regulatory factors. In addition, the genetic manipulation of embryo stem cells affords a unique avenue for experimental intervention in mammalian development and for controlled modification of the mouse germ line.

Studies on the fate of lymphocytes. III. The migration and metamorphosis of in situ labeled thymic lymphocytes

The in situ thymus of the guinea pig was labeled locally with H3-thymidine and sections of various tissues analyzed by radioautography for the location of labeled cells which might have left the thymus from 30 minutes to three days after labeling. Labeled lymphocytes were located especially in the mesenteric lymph nodes and spleen, giving direct evidence for the migration of thymocytes under near-physiological conditions. Only a few cells were found in the bone marrow, and none in the liver. The identified cells were not seen to be undergoing subsequent proliferation, but about one-fourth of them were transforming to other cell types - plasma cells, heterophil granulocytes, reticular cells, and macrophages. The fate of another portion of the cells seemed to be loss to the gut lumen through the mucosa. These data suggest that a normal function of the thymus of the adult guinea pig is the proliferation of a population of pluripotential stem cells which, after migration to other tissues, may further differentiate under appropriate stimulus. Possible applications of the local labeling technique are indicated.

STUDIES ON THE FATE OF LYMPHOCYTES. 3. THE MIGRATION AND METAMORPHOSIS OF IN SITU LABELED THYMIC LYMPHOCYTES.

AbstractThe in situ thymus of the guinea pig was labeled locally with H3‐thymidine and sections of various tissues analyzed by radioautography for the location of labeled cells which might have left the thymus from 30 minutes to three days after labeling. Labeled lymphocytes were located especially in the mesenteric lymph nodes and spleen, giving direct evidence for the migration of thymocytes under near‐physiological conditions. Only a few cells were found in the bone marrow, and none in the liver. The identified cells were not seen to be undergoing subsequent proliferation, but about one‐fourth of them were transforming to other cell types ‐ plasma cells, heterophil granulocytes, reticular cells, and macrophages. The fate of another portion of the cells seemed to be loss to the gut lumen through the mucosa. These data suggest that a normal function of the thymus of the adult guinea pig is the proliferation of a population of pluripotential stem cells which, after migration to other tissues, may further differentiate under appropriate stimulus. Possible applications of the local labeling technique are indicated.