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Introduction: Hematopoietic stem/progenitor cells (HSPCs) reside in a tightly controlled local microenvironment called bone marrow niche. The specialized microenvironment or niche not only provides a favorable habitat for HSPC maintenance and development but also governs stem cell function., Method: We investigated the effect of cytotoxic drugs on bone marrow niche. To mimic the multiple rounds of chemotherapy followed by autologous hematopoietic stem cells (HSCs) transplantation in a clinical setting, we further verified the hypothesis that targeting the niche might improve stem cell-based therapies in mouse models., Results: We found that multiple rounds of cytotoxic drug treatment significantly disrupted niche and serum osteocalcin level was significantly reduced after treatment in autologous HSPCs transplanted patients (P = 0.01). In mouse models, the number of CD45(-)Ter119(-)OPN(+) osteoblasts was significantly reduced after multiple rounds of chemotherapies and granulocyte colony stimulating factor (G-CSF) treatment (P < 0.01). Parathyroid hormone (PTH) or receptor activator of nuclear factor kappa-B ligand (RANKL) treatment significantly increased the number of HSCs mobilized into peripheral blood (PB) for stem cell harvesting and protected stem cells from repeated exposure to cytotoxic chemotherapy. Treatments with G-CSF and PTH significantly increased the preservation of the HSC pool (P < 0.05). Moreover, recipient mice transplanted with circulation HSPCs that were previously treated with PTH and RANKL showed robust myeloid and lymphatic cell engraftment compared to the mice transplanted with HSCs after chemotherapy or G-CSF treatment., Conclusion: These data provide new evidence that the niche may be an important target for drug-based stem cell therapy.

The majority of hematopoietic stem/progenitor cells (HSPCs) reside in bone marrow (BM) surrounded by a specialized environment, which governs HSPC function. Here we investigated the potential role of bone remodeling cells (osteoblasts and osteoclasts) in homeostasis and stress-induced HSPC mobilization. Peripheral blood (PB) and BM in steady/mobilized state were collected from healthy donors undergoing allogeneic transplantation and from mice treated with granulocyte colony stimulating factor (G-CSF), parathyroid hormone (PTH), or receptor activator of nuclear factor kappa-B ligand (RANKL). The number and the functional markers of osteoblasts and osteoclasts were checked by a series of experiments. Our data showed that the number of CD45(-) Ter119(-) osteopontin (OPN)(+) osteoblasts was significantly reduced from 4,085 ± 135 cells/femur on Day 0 to 1,032 ± 55 cells/femur on Day 5 in mice (P = 0.02) and from 21.38 ± 0.66 on Day 0 to 14.78 ± 0.65 on Day 5 in healthy donors (P < 0.01). Decrease of osteoblast number leads to reduced level of HSPC mobilization regulators stromal cell-derived factor-1 (SDF-1), stem cell factor (SCF), and OPN. The osteoclast number at bone surface (OC.N/B.s) was significantly increased from 1.53 ± 0.12 on Day 0 to 4.42 ± 0.46 on Day 5 (P < 0.01) in G-CSF-treated mice and from 0.88 ± 0.20 on Day 0 to 3.24 ± 0.31 on Day 5 (P < 0.01) in human. Serum TRACP-5b level showed a biphasic trend during G-CSF treatment. The ratio of osteoblasts number per bone surface (OB.N/B.s) to OC.N/B.s was changed after adding PTH plus RANKL during G-CSF treatment. In conclusion, short term G-CSF treatment leads to reduction of osteoblasts and stimulation of osteoclasts, and interrupting bone remodeling balance may contribute to HSPC mobilization., (Copyright © 2012 Wiley Periodicals, Inc.)

The long-term survival of patients with acute myeloid leukemia (AML) is dismally poor. A permanent cure of AML requires elimination of leukemic stem cells (LSCs), the only cell type capable of initiating and maintaining the leukemic clonal hierarchy. We report a therapeutic approach using an activating monoclonal antibody directed to the adhesion molecule CD44. In vivo administration of this antibody to nonobese diabetic-severe combined immune-deficient mice transplanted with human AML markedly reduced leukemic repopulation. Absence of leukemia in serially transplanted mice demonstrated that AML LSCs are directly targeted. Mechanisms underlying this eradication included interference with transport to stem cell–supportive microenvironmental niches and alteration of AML-LSC fate, identifying CD44 as a key regulator of AML LSCs. The finding that AML LSCs require interaction with a niche to maintain their stem cell properties provides a therapeutic strategy to eliminate quiescent AML LSCs and may be applicable to other types of cancer stem cells. [ABSTRACT FROM AUTHOR]