Micro-Environmental Regulation of Stem Cells <

	3.03.2009 SPEAKER: David Scadden, MD: Harvard University, MGH MODERATOR: Charles A. Vacanti, MD: HMS, BWH

Forum Summary

All cells are affected by the environment in which they reside, and stem cells are no exception.  Stem cells are capable of proliferation and self-renewal, but they can also become malignant.  The niche hypothesis states that a stem cell’s development is regulated through the cell’s interaction with its micro-environment, or niche.  As first discussed by Schofield, a niche can be defined as a specialized anatomical location with the ability to regulate the proliferation and differentiation of stem cells.  After Schofield proposed the idea of a niche, studies in fruit flies confirmed that such niches do exist.  The hematopoietic system can be used as a representative system for studying the role that a stem cell’s micro-environment plays in its development.

Hematopoietic stem cells in the flat bones of the skulls of mice can be visualized in vivo using two-photon confocal microscopy, and recent studies have revealed that these stem cells occupy specific locations within bones.  They tend to reside close to blood vessels and bone-forming cells called osteoblasts.  More primitive stem cells seem to reside closer to osteoblasts than do less primitive cells.  These observations suggest that osteoblasts are a key participant in the regulation of stem cells.  Stem cells tend to co-localize with the cytokine CXCL12, and interfering with this cytokine limits the effectiveness of bone marrow transplants in mice.  Parathyroid hormone (PTH), on the other hand, seems to improve stem cell grafting.

When a stem cell’s niche goes bad, health problems can be the result.  Micro RNA’s are small RNA molecules that regulate gene expression, and these RNA molecules are sometimes processed by an enzyme called DICER.  The elimination of DICER affects cell development and differentiation.  It has been shown that the conditional deletion of DICER in osteoblast precursors affects the regulation of wild-type stem cells.  Mice in which DICER was deleted only in osteoblast precursors exhibited symptoms similar to those produced by myelodysplasia in humans.  Stem cell proliferation increased, but so did cell death, or apoptosis.  Deleting DICER in older osteoblasts had no effect on stem cells.  Thus, it seems that osteoblast precursors are an important component of the niche of stem cell and that the disruption of a niche can cause dysplasia and neoplasia.    

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