Lab Sheds Light on Maintenance of Blood-Forming Stem Cells (4/19/2008)

The Stowers Institute's Linheng Li Lab has clarified the role of the adhesion molecule N-cadherin in the maintenance of blood-forming cells in the bone marrow, called hematopoietic stem cells (HSCs).

N-cadherin anchors HSCs to their niches - the microenvironments in which they are nurtured. The Linheng Li Lab has demonstrated that it also plays a critical role in controlling the balance between the regeneration of blood cells and long term maintenance of HSCs.

In normal homeostatic state, HSCs are relatively inactive. However, one hallmark of HSCs is their ability to rapidly proliferate in response to stresses such as myelosuppressive chemotherapy or bone marrow transplantation in order to replace the ablated hematopoietic system. This process also requires a delicate balance because, at the same time, HSCs must avoid excess cell division, which can lead to cellular exhaustion and the accumulation of mutations.

In findings published to the Web site of the journal Cell Stem Cell on April 9, the Li Lab demonstrated that varying N-cadherin levels distinguish two subpopulations of cells in a pool of "primitive" HSCs that support long-term blood production.

Low levels of N-cadherin correspond with HSCs in a "primed" state that are ready to support active blood regeneration and to mobilize in the blood. Cells with intermediate levels of N-cadherin form a larger pool of "reserved" HSCs that have a lower cell cycle entry rate and lower metabolic activity, and, therefore, serve a maintenance role in the blood.

"The balance between regeneration of blood cells and maintenance of stem cells is achieved in part by having different sets of HSCs assigned to these tasks, each with a distinctive molecular signature," said Xi He, M.D., Senior Research Specialist and co-equal first author on the paper. "We have demonstrated that differential N-cadherin expression level reflects functional distinctions between two HSCs sub-populations that are essential for replenishing a healthy blood supply under stress."

The Stowers Institute's Cytometry Facility collaborated on the work.

"This manuscript is the result of a wonderful collaboration with Linheng Li's Laboratory," said Jeff Haug, Managing Director - Cytometry Facility and co-equal first author on the paper. "Using the advanced technology of the Cytometry Facility, we were able to design and perform cytometric experiments that led to the discovery and isolation of 'reserved' and 'primed' hematopoietic stem cells - an exciting advancement."

"The improved understanding of N-cadherin on HSCs is potentially clinically important for a number of reasons," said Linheng Li, Ph.D., Associate Investigator and senior author on the paper. "We've shown that primed HSCs regenerate blood cells very effectively, which may be useful knowledge for improving transplantation. Additionally, recognition that a larger pool of HSCs are in a reserved state may ultimately help clinicians therapeutically utilize or protect them. For example, combination of 'primed' and 'reserved' HSCs in transplantation therapy may help to provide both rapid reconstitution and long-term maintenance of the hematopoietic system. Finally, it is possible that cancers may involve two kinds of cancer stem cells, one more latent and the other more active - but both involved in cancer growth in different ways. I believe this work opens a number of significant doors for future research in these areas."

Additional contributing authors from the Stowers Institute include Justin Grindley, Ph.D., Senior Research Associate; Joshua Wunderlich, Research Technician III; Karin Gaudenz, Ph.D., Research Specialist II; Jason Ross, Predoctoral Researcher; Ariel Paulson, Programmer Analyst I; Kathryn Wagner, Research Technician II; Yucai Xie, Predoctoral Research Associate; Ruihong Zhu, Research Technician II; Tong Yin, Ph.D., Postdoctoral Research Associate; John Perry, Ph.D., Postdoctoral Research Associate; Mark Hembree, Laboratory Manager I; Erin Redenbaugh, Research Technician II; and Christopher Seidel, Ph.D., Managing Director - Microarray.

Also contributing was Glenn Radice, Ph.D., Center for Research on Reproduction and Women's Health, Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine.

Note: This story has been adapted from a news release issued by the Stowers Institute for Medical Research

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