Researchers create first functional stem cell niche

Irving Weissman

Like it or not, your living room says a lot about you. Given a few moments to poke around, a stranger could get a good idea of your likes and dislikes, and maybe even your future plans. Medical school scientists, employing a similar "peeping Tom" tactic to learn more about how stem cells develop, have taken a significant step forward by devising a way to re­create the cells' lair—a microenvironment called a niche—in an animal.

"We've isolated the cells in mouse bone that make bone and cartilage from scratch and attract wandering blood stem cells," said Irving Weissman, MD, the Virginia & D.K. Ludwig Professor for Clinical Investigation in Cancer Research and director of Stanford's Stem Cell Biology and Regenerative Medicine Institute. "The stem cells settle in these niches and make blood that is exported to the body."

This is the first time that scientists have created a functional stem-cell niche for further study. They plan to use the system to determine how niches interact with blood stem cells to affect their development, and how leukemias respond to these niches. They will also study these cells' capacity to heal bone and cartilage.

Weissman is senior author of the study, published Dec.10 in the advance online issue of Nature. Graduate student Charles Chan and postdoctoral scholars Ching-Cheng Chen, PhD, and Cynthia Luppen, PhD, share first authorship.

Blood-forming stem cells typically reside in the bone marrow. The researchers found that a specific subset of fetal mouse bone cells could not only take up residence and produce bone when injected near the kidney of a mouse, but they also generated a bone marrow cavity that sheltered host-derived blood stem cells. In contrast, other subsets of fetal bone cells generated only bone.

"An amazing part of this study was the formation of organized bone, cartilage and blood stem cell niches from an initially dispersed set of cells," said Weissman, also a member of the Stanford Cancer Center. "If we can find the daughter cell responsible for niche formation, we may eventually be able to expand blood stem cell numbers so that a small number, say from umbilical cord blood, can be made into enough to treat several patients with failure of blood formation."

Suppressing the expression of factors involved in a specialized bone-building process called endochondrial ossification in the host mouse stopped the formation of the marrow cavity and the recruitment of host stem cells. Using similar fetal bone cells from parts of the skeleton that do not undergo the process—such as the skull and the jaw—also blocks cavity formation. The findings suggest that endochondrial ossification is a necessary step to set up house for stem cells.

The study involved postdoctoral scholar Jae-Beom Kim, PhD; associate professor of surgery Jill Helms, DDS, PhD; associate professor of medicine Calvin Kuo, MD, PhD; and senior postdoctoral fellow Daniel Kraft, MD. It was funded by the NIH and Hope Street Kids.