title: Targeting stem cell niche can protect hematopoietic stem cells from chemotherapy and G-CSF treatment.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  These data provide new evidence that the niche may be an important target for drug-based stem cell therapy.
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union of Medical College, 288 Nanjing Road, Tianjin, 30020, China. lisidan2006@126.com.|Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics, Ministry of Education, Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, Beijing, China. lisidan2006@126.com.
authors.forename: Sidan
authors.initials: S
authors.lastname: Li
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union of Medical College, 288 Nanjing Road, Tianjin, 30020, China. zoudehui@126.com.
authors.forename: Dehui
authors.initials: D
authors.lastname: Zou
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union of Medical College, 288 Nanjing Road, Tianjin, 30020, China. leewa@163.com.
authors.forename: Changhong
authors.initials: C
authors.lastname: Li
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union of Medical College, 288 Nanjing Road, Tianjin, 30020, China. mhx333@aliyun.com.
authors.forename: Hengxing
authors.initials: H
authors.lastname: Meng
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union of Medical College, 288 Nanjing Road, Tianjin, 30020, China. suiweiwei@126.com.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Sui
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union of Medical College, 288 Nanjing Road, Tianjin, 30020, China. sizhoufeng@yahoo.com.
authors.forename: Sizhou
authors.initials: S
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union of Medical College, 288 Nanjing Road, Tianjin, 30020, China. hengtao@ihcams.ac.cn.
authors.forename: Tao
authors.initials: T
authors.lastname: Cheng
authors.affiliation: Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China. qionglizhai@hotmail.com.
authors.forename: Qiongli
authors.initials: Q
authors.lastname: Zhai
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union of Medical College, 288 Nanjing Road, Tianjin, 30020, China. drqiu99@medmail.com.cn.
authors.forename: Lugui
authors.initials: L
authors.lastname: Qiu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002478:Cells, Cultured; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010281:Parathyroid Hormone / Q000494:pharmacology; D053245:RANK Ligand / Q000494:pharmacology; D055153:Stem Cell Niche
chemical_list: D000970:Antineoplastic Agents; D010281:Parathyroid Hormone; D053245:RANK Ligand; D016179:Granulocyte Colony-Stimulating Factor