干细胞的renewal和differentiation or matureation都是由其周围的微环境有关。bone marrow mesenchymal stem cell能持续存在于骨髓中不仅为造血干细胞提供feeder环境，同时也为自身提供一个niche。神经干细胞在神经系统内几乎不增殖，只有当神经出现损伤时，才有可能被激活，因为在正常的神经系统微环境中，只允许它存在，但不允许它激活，而一旦出一损伤，微环境的改变则有可能激活它。最近发现的心脏干细胞（最近的cell)，同样也揭示这一点，平时心脏干细胞不具有增殖能力，只有必要时候它才分化。同样ES cell分化，甚至胚胎发育过程中，许多现象都是微环境有关，如不同蛋白的梯度分布，可以决定胚胎组织的不同方向分化和生长。但微环境只是一个粗概念，微环境中什么因子起作用，是一个决定性因子，还是一群因子共同作用？如维持小鼠ES cell的 renewal主要是LIF因子，那么其它因子难道没有作用，当然不是。那么这些因子又是如何作用？在in vitro环境中如何模拟in vivo的微环境？都是今后要深入研究的问题。（编辑：Bioon）
Nature 425, 778 - 779 (23 October 2003); doi:10.1038/425778a
Stem cells: Interactive niches
IHOR R. LEMISCHKA AND KATERI A. MOORE
1 Ihor R. Lemischka and Kateri A. Moore are in the Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA.
e-mail: ilemischka@molbio.princeton.edu
The microenvironment, or niche, in which stem cells reside controls their renewal and maturation. The niche that regulates blood-forming stem cells in adult animals has eluded researchers — until now.
Cell-fate decisions in the developing embryo are governed by a complex interplay between cell-autonomous signals and stimuli from the surrounding tissue — the microenvironment. Similar processes control the birth and maturation of stem cells that replenish mature cell populations in adults1, 2. But where are the stem-cell microenvironments located in adult tissues? And what other cell types contribute to these 'niches'? In mammals, the niches for gut and certain skin stem cells have been pinpointed, and in several cases the molecular signals that emanate from them have been identified3-6. Somewhat ironically, however, the niches that interact with the best-characterized mammalian stem cells, the haematopoietic stem cells (HSCs), which replenish at least ten blood-cell lineages, have been much more elusive. In this issue, Zhang et al.7 and Calvi et al.8 now provide insights into the nature of HSC niches in adult animals. These authors demonstrate that osteoblasts — cells that reside in the bone marrow and secrete the calcified bone matrix — have a crucial role in HSC regulation.
Several studies have suggested that primitive HSCs reside next to the inner surface of bone and that they migrate towards the blood vessels at the centre of the bone marrow cavity as they mature and 'differentiate'9, 10. Since the 1970s, efforts to characterize the HSC niche have involved developing systems in vitro that might mimic some of the features of stem cell–niche interactions in vivo11. Indeed, single clones of 'stromal' cells can support HSC self-renewal and differentiation in culture12. And some of these stromal cell clones are part of the bone-forming 'osteoblastic' lineage, which is consistent with the idea that osteoblasts might be a component of the HSC niche in vivo13.
Zhang et al.7 and Calvi et al.8 have now confirmed that osteoblasts have a function in stem-cell regulation in animals. Both groups employed genetic strategies to increase the size of the osteoblast population in specific regions of bone. They then looked at how this affected the HSC population. In essence, they found that increasing the number of osteoblasts causes parallel increases in the HSC population.
Zhang et al.7 looked at the involvement of signalling by bone morphogenetic protein (BMP) in HSC regulation. The activity of BMP is crucial to the development of blood-forming tissue in embryos. The authors show that mutant mice depleted of a cellular receptor for BMP develop bone abnormalities — calcified 'trabecular bone-like areas' form within long bones. And the numbers of primitive long-term (LT) HSCs are approximately doubled in these animals. The authors go to considerable lengths to demonstrate that the HSC pool is specifically increased without concomitant increases in other primitive progenitor cell populations. Such a specific increase in only the LT-HSC population is consistent with very local effects; in other words, it suggests that a very specific niche is functionally enhanced.
To gain further insight, the authors employed a more elaborate genetic strategy in which a fluorescent green protein marker was activated in cells that were depleted of the BMP receptor. Only the osteoblasts that lined the surface of the bone-like area fluoresced. Using a combination of cell markers to label the LT-HSCs, Zhang et al. found that the stem cells co-localized with spindle-shaped osteoblasts lining the bone surface. And a doubling of this osteoblast population mirrored the increase in the LT-HSC population in the mutant mice. These osteoblasts, and a subpopulation of the HSCs, expressed N-cadherin, a cell-surface molecule that helps cells adhere to one another. The authors suggest that N-cadherin and a protein that forms a complex with it, -catenin, might form important components of the interaction between the stem cell and its niche. To prove this, it will be necessary to show that N-cadherin is expressed by functional LT-HSCs.
Calvi et al.8 arrive at some of the same conclusions but with a different approach. These authors also used a genetic strategy to increase osteoblast numbers in genetically engineered mice — but in this case, the osteoblasts of these mutant mice overproduced a cellular receptor that enhanced their growth. The resulting increases in the number of osteoblasts matched increases in the HSC population. Again, the authors showed that only the LT-HSC population increased in size and that other, more committed, progenitor populations were unchanged. To prove that microenvironmental signals caused the HSC population to expand, the authors used an in vitro test. They found that cultured stromal cells taken from the genetically engineered animals were better able to support HSCs than were stromal cells taken from normal animals.
Additional experiments implicated the 'Notch' signalling pathway in the expansion of the HSC population in the transgenic animals. This pathway is widely used in many organisms to regulate cell-fate decisions. Osteoblasts from the transgenic mice produced higher than normal levels of Jagged1 — a ligand for the Notch receptor — whereas the HSCs showed corresponding increases in the levels of the activated intracellular portion of this receptor. Furthermore, an inhibitor of the Notch pathway abrogated the ability of transgenic stromal cells to support HSCs in culture. Finally, when the authors administered parathyroid hormone to normal mice to increase the osteoblast cell population, the HSC population also increased in size. This strategy might prove to have future clinical value.
How precisely is the HSC niche defined by these two studies? It is not yet delineated as clearly as the niches for mammalian gut or skin stem cells, or the embryonic 'germ-line' cells of the fruitfly Drosophila. In these systems the structure of the tissue facilitates the identification of stem cells and their immediate progeny. Determining the location of short-term HSC cells and of HSC progeny will be important, as will identifying the molecular signals that emanate from the niche. A fluorescent 'reporter' system has been used to reveal the reception of 'Wnt' signals by HSCs — similar approaches could be used to investigate other signalling pathways, such as the Notch pathway, in the HSC niche14.
Zhang et al.7 and Calvi et al.8 clearly implicate osteoblasts as components of the HSC niche (Fig. 1), but other cell types might also be involved. In addition, it should be kept in mind that generic terms such as 'osteoblasts', 'endothelial cells' and 'fibroblasts' (other cell types in bone marrow) do not imply that all cells in these categories are identical15. In future studies it will be important to determine the exact molecular characteristics of the osteoblasts that contact HSCs and thus contribute to the maintenance and renewal of virtually all the cells of the blood.
Figure 1 Birth control for stem cells. Full legend
High resolution image and legend (71k)
