thymocytesStuffed with duck as I am (we don’t do turkey for Thanksgiving in our house) I’m not up to a long post, but I thought a paper in the latest issue of Science was pretty cool. The paper is
Czechowicz, A., Kraft, D., Weissman, I. L., and Bhattacharya, D. (2007). Efficient Transplantation via Antibody-Based Clearance of Hematopoietic Stem Cell Niches. Science 318, 1296-1299. 1

Very briefly, they show that one of the obstacles to bone marrow grafts — even in the absence of host-versus-graft immunity — is that there are a limited number of niches for hematopoietic (bone marrow) stem cells. The native stem cells occupy those niches, so injecting in a donor’s stem cells is very inefficient; only a tiny number can find a home and supply new, desirable progeny. If I’m interpreting the data right, there seem to be only a few hundred open slots, out of maybe 25000 total slots, available for donor stem cells.

Blogging on Peer-Reviewed ResearchThey came up with a protocol that transiently and specifically eliminated host stem cells — opening up niches — before the graft, and the results were pretty dramatic. Without treatment, the chimerism rates (indicating efficiency of donor engraftment) was around 3%; with treatment, it was 90%. If this works in humans as it does in mice, it offers a much gentler alternative to the really brutal and toxic treatments that are usually necessary today.

So what does “niche” mean, in this context? Is it a physical slot into which the tab of a hematopoietic stem cell is tucked? Is it a conceptual niche, a constraint based on available levels of some soluble factor, or on rates of contact with some supporting cell type? I think all three are possible, and2 have parallels in other aspects of the immune system.

For example, growth in the thymus (the figure at top left) probably requires physical niches, cells into which developing thymocytes cuddle up and receive nourishment and advice as they mature. (See, especially, the videos taken by Bousso et al, 3 of thymocytes interacting with thymic stromal cells.) Although I admit I find that the most attractive concept, I don’t really have a good reason for it, and there are probably good examples of non-physical “niches” as well. Survival of naïve lymphocytes outside of the periphery requires intermittent contact with MHC class I molecules — potentially a limiting factor, if they have to compete with others of their kind. There are also several examples of regulation by limiting amounts of certain cytokines, such as IL-7. 4 Still, the various two-photon microscopy videos of in-situ interactions that have been coming out over the past few years have really made me appreciate the importance of physical location and direct interactions in the immune system, which might explain my bias toward physical niches.

  1. As an experiment in aggregation, I am including a second version of the reference here, thus: Czechowicz, A., Kraft, D., Weissman, I.L., Bhattacharya, D. (2007). Efficient Transplantation via Antibody-Based Clearance of Hematopoietic Stem Cell Niches. Science, 318, 1296-1299. DOI: 10.1126/science.1149726[]
  2. According to current understanding, anyway[]
  3. Bousso, P., Bhakta, N. R., Lewis, R. S., and Robey, E. (2002). Dynamics of thymocyte-stromal cell interactions visualized by two-photon microscopy. Science 296, 1876-1880. []
  4. Purton, J. F., Tan, J. T., Rubinstein, M. P., Kim, D. M., Sprent, J., and Surh, C. D. (2007). Antiviral CD4+ memory T cells are IL-15 dependent. J Exp Med 204, 951-961. []