Hematopoietic Stem Cells Go New Age:
Niches and Renewal of Self

By Derek M. Persons, M.D., Ph.D.

The location of hematopoietic stem cells in the bone marrow microenvironment may be integrally related to the mechanisms underlying their regulation. It has long been known that marrow near endosteal surfaces is highly enriched for stem cells. Thus, local environmental cues mediated by cells such as osteoblasts may be one way in which stem cell activity is regulated. A series of presentations in the Hematopoietic Microenviroment Simultaneous Session yesterday (4:45 p.m. – 5:45 p.m.) provided evidence that marrow osteoblasts, stromal cells, and monocytes are important players in regulating stem cell fate decisions.

Two groups presented data that support the idea that bone marrow osteoblasts are key cells in regulating stem cell number. Drs. Li, Zhang, and colleagues (Abstract 51) reported that both the intratrabecular bone volume and stem cell number is increased in mutant mice containing a conditional inactivation of the bone morphogenic protein (BMP) receptor type I. These mutant mice also had an increase in spindle-shaped, N-cadherin+ CD45- osteoblastic cells. Furthermore, these osteoblastic cells appeared to be in direct contact with cells having long-term hematopoietic repopulating activity, suggesting a link between the BMP signaling in osteoblasts and regulation of stem cell number. Drs. Adams, Calvi, and colleagues (Abstract 52) also presented data implicating osteoblasts in regulating stem cell number. They reported that mice containing a constitutively active parathyroid hormone/parathryroid hormone related peptide receptor displayed an increase in stem cell number. Increased Jagged 1 expression was found on the activated osteoblasts and evidence was presented to implicate Jagged 1-mediated Notch 1 signaling in causing the increase in stem cell numbers. Interestingly, Drs. Iwata, Awaya, and colleagues (Abstract 53) reported that monocytes may modulate the ability of human CD34+ cells to interact with stromal cells. Data was shown that suggested that soluble factor secretion by stromal cells can activate monocytes to increase osteopontin expression, which in turn may lead to downregulation of Notch 1 on stem cells. This may result in directing stem cell fate toward differentiation. Thus, it appears that a complex signaling network involving osteogenic cells, stromal cells, monocytes, and stem cells may regulate stem cell fate decisions.

Today, in the Regulation of HSC Self-Renewal Simultaneous Session (11:00 a.m. – 12:30 p.m.), the focus will turn to intracellular, downstream molecules as part of the complex network of stem cell regulators. Drs. Krosl, Austin, and colleagues (Abstract 321) will present data demonstrating the ability of a TAT-HOXB4 fusion protein to mediate in vitro expansion of murine, long-term repopulating stem cells. Sca+Lin- bone marrow cells cultured for four days in media containing the TATHOXB4 protein showed up to a 7-fold increase in repopulating stem cell activity, suggesting that this may be a useful method to increase the number of stem cells for therapeutic purposes. In work by Drs. Walkey, Purton, and colleagues (Abstract 324), the effects of loss of the Myc-antagonist Mad1 and the CDK inhibitor p27kip1 will be presented. Mice nullizygous for both Mad1 and p27 showed a 7-fold increase in stem cell frequency and, unlike wildtype or singly nullizygous mice, their stem cells could be serially transplanted. These phenotypic changes may be due to an increase in the cycling frequency. Finally, Drs. Yuan, Shields, and colleagues will present data (Abstract 326) which suggests that the CDK inhibitor p18Ink4C plays a role in determining the likelihood of symmetric versus asymmetric stem cell divisions. Mice lacking p18 were found to have an increased number of stem cells as determined by limiting dilution analysis. However, this increase in stem cell number was not associated with an increased rate of cell division. Data will be presented addressing whether p18 null stem cells have a higher rate of symmetric divisions using single cell transplantation experiments.