title: Mechanical unloading of bone in microgravity reduces mesenchymal and hematopoietic stem cell-mediated tissue regeneration.
abstract: Mechanical loading of mammalian tissues is a potent promoter of tissue growth and regeneration, whilst unloading in microgravity can cause reduced tissue regeneration, possibly through effects on stem cell tissue progenitors. To test the specific hypothesis that mechanical unloading alters differentiation of bone marrow mesenchymal and hematopoietic stem cell lineages, we studied cellular and molecular aspects of how bone marrow in the mouse proximal femur responds to unloading in microgravity. Trabecular and cortical endosteal bone surfaces in the femoral head underwent significant bone resorption in microgravity, enlarging the marrow cavity. Cells isolated from the femoral head marrow compartment showed significant down-regulation of gene expression markers for early mesenchymal and hematopoietic differentiation, including FUT1(-6.72), CSF2(-3.30), CD90(-3.33), PTPRC(-2.79), and GDF15(-2.45), but not stem cell markers, such as SOX2. At the cellular level, in situ histological analysis revealed decreased megakaryocyte numbers whilst erythrocytes were increased 2.33 fold. Furthermore, erythrocytes displayed elevated fucosylation and clustering adjacent to sinuses forming the marrow-blood barrier, possibly providing a mechanistic basis for explaining spaceflight anemia. Culture of isolated bone marrow cells immediately after microgravity exposure increased the marrow progenitor's potential for mesenchymal differentiation into in-vitro mineralized bone nodules, and hematopoietic differentiation into osteoclasts, suggesting an accumulation of undifferentiated progenitors during exposure to microgravity. These results support the idea that mechanical unloading of mammalian tissues in microgravity is a strong inhibitor of tissue growth and regeneration mechanisms, acting at the level of early mesenchymal and hematopoietic stem cell differentiation.
authors.affiliation: School of Biotechnology and Bimolecular Sciences, University of New South Wales, Sydney, Australia; Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Blaber
authors.affiliation: Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Dvorochkin
authors.affiliation: Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA, USA; Department of Bioengineering, Santa Clara University, Santa Clara, CA, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Torres
authors.affiliation: Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Yousuf
authors.affiliation: School of Biotechnology and Bimolecular Sciences, University of New South Wales, Sydney, Australia.
authors.forename: B P
authors.initials: BP
authors.lastname: Burns
authors.affiliation: Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Globus
authors.affiliation: Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA, USA. Electronic address: e.almeida@nasa.gov.
authors.forename: E A C
authors.initials: EA
authors.lastname: Almeida
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001696:Biomechanical Phenomena; D001861:Bone Regeneration; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D002454:Cell Differentiation; D002478:Cells, Cultured; D005260:Female; D005270:Femur Head / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D018507:Gene Expression Regulation, Developmental; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D044968:Regenerative Medicine / Q000379:methods*; D013314:Stress, Mechanical; D013997:Time Factors; D023822:Tissue Engineering; D016474:Weight-Bearing; D018474:Weightlessness Simulation
chemical_list: D015415:Biomarkers