Therapeutic targeting of a stem cell niche

Abstract

The specialized microenvironment or niche where stem cells reside provides regulatory input governing stem cell function. We tested the hypothesis that targeting the niche might improve stem cell-based therapies using three mouse models that are relevant to clinical uses of hematopoietic stem (HS) cells. We and others previously identified the osteoblast as a component of the adult HS cell niche and established that activation of the parathyroid hormone (PTH) receptor on osteoblasts increases stem cell number. Here we show that pharmacologic use of PTH increases the number of HS cells mobilized into the peripheral blood for stem cell harvests, protects stem cells from repeated exposure to cytotoxic chemotherapy and expands stem cells in transplant recipients. These data provide evidence that the niche may be an attractive target for drug-based stem cell therapeutics.

Parathyroid hormone regulates the distribution and osteoclastogenic potential of hematopoietic progenitors in the bone marrow

“…The effects of PTH on hematopoietic progenitors from bone marrow and peripheral blood have been described previously. (20,31) However, to our knowledge, this study is the first to report the effect of PTH on cells in the spleen. We observed a significant increase in the percentage but not the absolute numbers of LKS cells and LT-HSCs on day 7 of PTH treatment.…”

“…This has led to the proposal that PTH treatment could be used as a more effective way to mobilize progenitors, facilitating their harvest from blood for hematopoietic stem cell-based therapies. (20) To test whether these effects also were evident in our experiments, we examined the effects of PTH treatment in vivo on days 7 and 14 on the percentages and absolute numbers of early hematopoietic precursors, as assessed by the phenotype Lin À CD117 þ Sca1 þ (LKS). As depicted in Fig.…”

“…Most studies have been focused on the effects of PTH on osteoblasts, and recent published literature has shown that PTH also could modulate hematopoietic parameters. (20) However, direct studies of the effects of PTH on osteoclast progenitor populations and osteoclast development have not been done in a comprehensive fashion. This is important because a complete understanding on how PTH modulates different cell types in the bone microenvironment is crucial for developing new strategies to treat osteoporosis and bone fractures, as well as designing stem cell-based therapies (ie, hematopoietic stem cell transplantation and mobilization and harvesting of hematopoietic progenitors).…”

“…This is important because a complete understanding on how PTH modulates different cell types in the bone microenvironment is crucial for developing new strategies to treat osteoporosis and bone fractures, as well as designing stem cell-based therapies (ie, hematopoietic stem cell transplantation and mobilization and harvesting of hematopoietic progenitors). (20)(21)(22)(23) We have identified a discrete population of cells containing most of the in vitro osteoclast precursor (OCP) activity in murine bone marrow. (24) In this study we examined whether these populations of OCPs were affected by in vivo administration of PTH to mice.…”

The Actin Polymerization Regulator WAVE2 Is Required for Early Bone Marrow Repopulation by Hematopoietic Stem Cells

“…In the setting of transplantation, HSCs must take several steps to achieve successful long-term engraftment, which include transendothelial migration into the BM cavity from circulation (homing), settling in the BM niche (lodging and retention), and intraniche proliferation and multilineage differentiation (repopulation). The interactions between HSCs and various extracellular elements affect these multistep processes [8].…”