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The role of extrinsic and intrinsic regulators in haemopoiesis

Abstract

Haemopoiesis requires a highly complex series of cellular events in which a small population of stem cells needs to generate continuously large populations of maturing cells. Normally, the diverse proliferative, differentiative, and maturation events required to achieve this occur with precision, which indicates that the regulatory mechanisms involved are complex. Control mechanisms tend to be intrinsic or extrinsic to the stem cells, or a combination of both. The external factors include the cell-cell interactions in the haemopoietic microenvironment, cytokines, haemopoietic growth factors and interleukins. Whilst intrinsic regulation is achieved due to the genetic factors; the expression of several transcription factors has been shown to be essential for haemopoietic cell development from the earliest stages. Determination of the control of haemopoietic stem cell proliferation kinetics is the critical factor for the regulation of haemopoietic cell production. However, information about the control of stem cell renewal versus differentiation, and how this might be manipulated to improve haemopoietic cell regeneration, is still not fully understood. Overall, extrinsic and intrinsic control mechanisms may be considered separately, but a picture is emerging of the integration of extracellular signaling, signal transduction, transcription factors and cell cycle control in the determination of stem cell fate.

At present, the arguments for and against particular models for haemopoiesis are based on circumstantial evidence. The availability of a large number of antigenic markers for haemopoietic cells at various stages of maturation allows the possibility to define and purify haemopoietic stem cells. Computational models, to predict stem cell systems and discern underlying regulatory mechanisms governing stem cell fate decisions, have been investigated (Viswanathan and Zandstra 2003). HSC were the system of choice to investigate mechanisms that regulate stem cell fate decisions, and have thus served as an experimental and computational model for other stem cells.

Overall, intrinsic and extrinsic control mechanisms may be considered separately, but a picture is emerging of the integration of extracellular signalling, signal transduction, transcription factors and cell cycle control in the determination of stem cell fate. It seems incorrect to regard the multiplicity of haematopoietic regulators as representing a highly redundant control system of dubious value. There is mounting evidence of the necessity to use regulator combinations to achieve certain types of cell production and of the higher efficiency of multiple regulatory factors, even when their actions appear to exhibit considerable overlap (Metcalf 1993). These advantages also include the ability to achieve more subtle localisation of cells produced and to achieve the complex mixtures of the cells required in certain situations.

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