Adult stem cells hold many promises for future clinical applications and regenerative medicine. The haematopoietic stem cell (HSC) is the best-characterized somatic stem cell so far, but in vitro expansion has been unsuccessful, limiting the future therapeutic potential of these cells. Here we review recent progress in characterizing the composition of the HSC bone-marrow microenvironment, known as the HSC niche. During homeostasis, HSCs, and therefore putative bone-marrow HSC niches, are located near bone surfaces or are associated with the sinusoidal endothelium. The molecular crosstalk between HSCs and the cellular constituents of these niches is thought to control the balance between HSC self-renewal and differentiation, indicating that future successful expansion of HSCs for therapeutic use will require three-dimensional reconstruction of a stem-cell-niche unit.

Bone-marrow haematopoietic-stem-cell niches

Publisher Summary This chapter discusses the formal genetics of mouse anemias and their significance for an analysis of patterns of mammalian gene action. It also describes normal hemopoietic development, homeostasis, and hemoglobin polymorphism. Anemias are classified into five categories—(1) anemias of maturation arrest, (2) anemias involving defects in iron utilization, (3) anemias involving greatly reduced erythrocyte life-span, (4) hemoglobinopathies, and (5) anemias almost secondary to genetically induced defects. During the total life of a mouse, including prenatal development, hemopoiesis takes place in four different sites. Although hemopoiesis continues in the liver until birth and for a brief time thereafter, hemopoiesis (largely myelopoiesis) commences in the spleen on fetal day 15 or 16 and in the marrow around the time of birth. Hematologically normal adult mice from many different inbred strains regularly produce more than one kind of hemoglobin. There is a widespread genetic polymorphism at both the Hba locus, determining the α-globin structure and the Hbb locus, determining the β-globin structure, and both the loci involve considerable genetic complexity.

Hereditary Anemias of the Mouse: A Review for Geneticists*

Cumulative reported evidence indicates that some fraction of limbal basal epithelial cells are the stem cells for corneal epithelial cell proliferation and differentiation. Limbal epithelium is therefore crucial in maintaining the cell mass of corneal epithelium under normal conditions and plays an important role in corneal epithelial wound healing. Deficiency or absence of limbal stem cells explains well the pathogenesis of several ocular surface disorders characterised by defective conjunctival transdifferentiation or conjunctivalisation of cornea. This paper reviews and updates the basic concept of stem cells, the reported findings of limbal stem cells for corneal epithelium, and their therapeutic applications. Through this review, one hopes to gain a more complete understanding and increase proficiency in treating these diseases.

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Concept and application of limbal stem cells.

Haematopoietic stem cell (HSC) niches are specialized microenvironments that contain stem cells and regulate their maintenance. Cells at the interface of bone and the bone marrow (the endosteum) contribute to the creation of HSC niches. It remains uncertain whether this interface itself is a niche, or whether endosteal cells secrete factors that diffuse to nearby niches. Vascular and/or perivascular cells may also create niches as many HSCs are observed around sinusoidal blood vessels, and perivascular cells secrete factors that regulate HSC maintenance. Do endosteal and perivascular cells create distinct niches, or do they contribute to a common niche? We discuss a range of niche models consistent with recent evidence.

Uncertainty in the niches that maintain haematopoietic stem cells

Blood and bone: two tissues whose fates are intertwined to create the hematopoietic stem-cell niche

Measurement of dna-synthesis time in myeloid-erythroid precursors.

SummaryThe formation of a new sinusoidal marrow in a heterotopic autologous marrow implant requires the intermediation of bone. This conclusion follows from the intimate association of developing marrow tissue and newly formed bone in the implantation site. It has been shown that there is a sigmoidal relationship between the evolution of a medullary cavity and ossicle volume. Moreover, the mean relative medullary cavity size and ossicle volume for each stage of marrow development from hemocytoblasts to a sinusoidal structure conforms to this relationship. Hematopoietic foci emerge during the period of rapid bone resorption. A fully developed marrow may occur in a small or large ossicle provided that the medullary cavity represents a critical fraction of the total volume. It is suggested that processes of bone resorption may contribute to the formation of an appropriate microenvironment and/or provide a source of appropriately modulated progenitor cells. Significantly, bone plays a necessary role in the ge...

Bone formation and resorption as a requirement for marrow development.

Cyclic hematopoiesis in grey collie dogs: a stem-cell problem.

Granulocyte transit from bone marrow to blood.

The restoration of marrow in a mechanically depleted segment of rabbit femur is locally determined and apparently initiated by cells normally resident in bone. This conclusion follows from results of two types of radiation experiments: local x-irradiation of the femur shaft immediately before depopulation and x-irradiation of the total body with exception of the femur diaphysis which was depopulated either just before or after irradiation. In contrast to the rapid initiation of marrow restoration in an unirradiated femur, there was little regeneration during the first 3 weeks in an irradiated femur. Recovery of the shielded depopulated femur in the rabbit that otherwise received total-body irradiation was similar to that in the unirradiated animal. Hence, it would appear that the seeding of circulating hemic stem cells is not essential to repopulation and that cells with hematopoietic potential are present in osseous tissue.

http://science.sciencemag.org/content/sci/165/3888/71.full.pdf

Mary A. Maloney

Papers

Measurement of dna-synthesis time in myeloid-erythroid precursors.

Bone formation and resorption as a requirement for marrow development.

Cyclic hematopoiesis in grey collie dogs: a stem-cell problem.

Granulocyte transit from bone marrow to blood.

Origin of repopulating cells after localized bone marrow depletion.