title: Human very small embryonic-like cells generate skeletal structures, in vivo.
abstract: Human very small embryonic-like (hVSEL) cells are a resident population of multipotent stem cells in the bone marrow involved in the turnover and regeneration of tissues. The levels of VSEL cells in blood are greatly increased in response to injury, and they have been shown to repair injured tissues. Adult hVSEL cells, SSEA-4(+)/CD133(+)/CXCR4(+)/Lin(-)/CD45(-), express the pluripotency markers (Oct-4 and Nanog) and may be able to differentiate into cells from all 3 germ lineages. hVSEL cells isolated from blood by apheresis following granulocyte-colony-stimulating factor mobilization were fractionated and enriched by elutriation and fluorescence activated cell sorting. Collagen sponge scaffolds containing 2,000-30,000 hVSEL cells were implanted into cranial defects generated in SCID mice. Analysis by microcomputed tomography showed that a cell population containing VSEL cells produced mineralized tissue within the cranial defects compared with controls at 3 months. Histologic studies showed significant bone formation and cellular organization within the defects compared with cellular or scaffold controls alone. Antibodies to human leukocyte antigens demonstrated that the newly generated tissues were of human origin. Moreover, human osteocalcin was identified circulating in the peripheral blood. There was evidence that some level of hVSEL cells migrated away from the defect site, using quantitative real-time polymerase chain reaction to detect for human-specific Alu sequences. This study demonstrates that hVSEL cells are able to generate human bone tissue in a mouse model of skeletal repair. These studies lay the foundation for future cell-based regenerative therapies for osseous and connective tissue disorders, including trauma and degenerative conditions, such as osteoporosis, fracture repair, and neoplastic repair.
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109-1078, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Havens
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Shiozawa
authors.forename: Younghun
authors.initials: Y
authors.lastname: Jung
authors.forename: Hongli
authors.initials: H
authors.lastname: Sun
authors.forename: Jincheng
authors.initials: J
authors.lastname: Wang
authors.forename: Samantha
authors.initials: S
authors.lastname: McGee
authors.forename: Anjali
authors.initials: A
authors.lastname: Mishra
authors.forename: L Susan
authors.initials: LS
authors.lastname: Taichman
authors.forename: Theodora
authors.initials: T
authors.lastname: Danciu
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Jiang
authors.forename: Gregory
authors.initials: G
authors.lastname: Yavanian
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Leary
authors.forename: Paul H
authors.initials: PH
authors.lastname: Krebsbach
authors.forename: Denis
authors.initials: D
authors.lastname: Rodgerson
authors.forename: Russell S
authors.initials: RS
authors.lastname: Taichman
mesh_terms: D000328:Adult; D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis; D001781:Blood Component Removal; D002465:Cell Movement; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010012:Osteogenesis; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation; D012886:Skull / Q000293:injuries* / Q000378:metabolism; D033581:Stem Cell Transplantation; D014183:Transplantation, Heterologous
chemical_list: D000943:Antigens, Differentiation