Blood-forming stem cells have recently garnered some attention. Genzyme’s drug to boost circulating stem cells in patients with blood cancers won FDA approval on Monday. Here is Genzyme’s description of its small molecule chemokine receptor antagonist. Also, two research teams from Stanford have found ways to make artificial versions of the microenvironments where blood forms (See below), and a third team from Germany and Switzerland describes away to track individual blood-forming stem cells .
But it’s not all bloody. Esophageal stem cells made the cover of the Journal of Clinical investigation. The cells lining your throat strike an “exquisite equilibrium between proliferation and differentiation.” Researchers led by Anil Rustgi at the University of Pennsylvania, used DNA-labeling to identify a population of slow-cycling, apparently self-renewing cells in the esophagus. Then they studied these cells in three-dimensional culture and found that they grew into esophageal structures. When these cells were placed in immunodeficient mice, they formed epithelial structures, and when they were placed in a mouse model of esophageal reflux disease, they migrated to the site of injury. Here’s the press release.
How to make a stem cell home: Making blood stem cell niches in vivo and in vitro
Two independent groups of researchers have made artificial versions of the stem cell niches where blood forms. Irving Weissman and colleagues at Stanford University in California found that with the right population of cells, bone can be made to grow in the kidney. What’s more, that bone can recruit a vasculature and establish a blood-forming niche, complete with haematopoietic stem cells. This marks the first in vivo assay to assess the formation and maintenance of a blood-forming niche at a site outside its natural location, and the researchers were able to use the assay to assess the ability of various soluble proteins to help establish the niche1.
The researchers tested different types of fetal bone cells to find a population capable of creating a stable niche. They sorted cells according to markers for mesenchymal stem cells (in this case, CD105 and Thy1.1). Populations expressing both markers could make bone, but these bones were not hollow and did not form marrow. However, populations expressing CD105 but not Thy1.1 did form bone with marrow when transplanted into recipient mice. Noting that the latter population passes through an intermediary cartilage stage before ossification, the researchers speculated that the reason the former population does not form marrow is related to the fact that these cells seem unable to form cartilage. Indeed, fetal cells expressing CD105 and Thy1.1 were unable to make marrow-containing bone in the transplants if the cells were derived from the developing skull and jaw — bones that form without a cartilage intermediate.
In separate work, Helen Blau, also of Stanford, and colleagues created an in vitro assay to study individual haematopoietic stem cells that were exposed to the proteins believed to reside within their niche, the microenvironment that maintains their stem-cell state2. By placing cells in patterned hydrogel microwells (tiny holes in a sophisticated Jell-O-like substance), the researchers were able to expose individual cells to both soluble proteins and to membrane-surface proteins that would be found on niche cells. Then they used time-lapse microscopy to watch if cells did nothing or divided slowly, rapidly, or asynchronously. They also carefully exposed cells to combinations of growth factors and cell-adhesion molecules, after which they transplanted the cells into irradiated mice. The division behavior of the cells in the microwells predicted their in vivo function as stem cells, and the system as a whole promises to be a technique that can be used to dissect the effects of various signals that occur in this niche. This could potentially allow the expansion of stem cells in vitro.
The ability to generate sufficient blood-forming stem cells has been a barrier to clinical applications. The effects of chemotherapies and several blood-forming diseases can be treated by re-seeding the blood-forming niche. Both a larger supply of cells and a better understanding of stem-cell maintenance could make such treatments more effective.
However, the knowledge could be broader, says Mick Bhatia, scientific head of the McMaster Stem Cell and Cancer Research Institute in Hamilton, Ontario, Canada. Both stem cell and niche react to each other as well as to distant hormones. The ability to create and manipulate artificial niches can help researchers explore such variation systematically and perhaps identify common mechanisms of how stem cells work within the niche.
1. Chan, C. K. F. et al. Endochondral ossification is required for haematopoietic stem-cell niche formation. Nature advance online publication, doi:10.1038/nature07547 (10 December 2008). | Article |
2. Lutolf, M. P. et al. Perturbation of single hematopoietic stem cell fates in artificial niches. Integr. Biol. doi:10.1039/b815718a (published online 21 November 2008). | Article |