title: CD31+ Cells From Peripheral Blood Facilitate Bone Regeneration in Biologically Impaired Conditions Through Combined Effects on Immunomodulation and Angiogenesis.
abstract: Controlled revascularization and inflammation are key elements regulating endogenous regeneration after (bone) tissue trauma. Peripheral blood-derived cell subsets, such as regulatory T-helper cells and circulating (endothelial) progenitor cells, respectively, can support endogenous tissue healing, whereas effector T cells that are associated with an aged immune system can hinder bone regeneration. CD31 is expressed by diverse leukocytes and is well recognized as a marker of circulating endothelial (precursor) cells; however, CD31 is absent from the surface of differentiated effector T cells. Thus, we hypothesized that by separating the inhibitory fractions from the supportive fractions of circulating cells within the peripheral blood (PB) using the CD31 marker, bone regeneration in biologically compromised conditions, such as those observed in aged patients, could be improved. In support of our hypothesis, we detected an inverse correlation between CD31+ cells and effector T cells in the hematomas of human fracture patients, dependent on the age of the patient. Furthermore, we demonstrated the regenerative capacity of human PB-CD31+ cells in vitro. These findings were translated to a clinically relevant rat model of impaired bone healing. The transplantation of rat PB-CD31+ cells advanced bone tissue restoration in vivo and was associated with an early anti-inflammatory response, the stimulation of (re)vascularization, and reduced fibrosis. Interestingly, the depletion or enrichment of the highly abundant CD31+/14+ monocytes from the mixed CD31+ cell population diminished tissue regeneration at different levels, suggesting combined effects within the PB-CD31+ subsets. In summary, an intraoperative enrichment of PB-CD31+ cells might be a novel option to facilitate endogenous regeneration under biologically impaired situations by supporting immunomodulation and vascularization. © 2016 American Society for Bone and Mineral Research.
authors.affiliation: Julius Wolff Institute (JWI) and Center for Musculoskeletal Surgery, Charité - University Medicine Berlin, Berlin, Germany.|Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: F Andrea
authors.initials: FA
authors.lastname: Sass
authors.affiliation: Julius Wolff Institute (JWI) and Center for Musculoskeletal Surgery, Charité - University Medicine Berlin, Berlin, Germany.|Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Schmidt-Bleek
authors.affiliation: Julius Wolff Institute (JWI) and Center for Musculoskeletal Surgery, Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Agnes
authors.initials: A
authors.lastname: Ellinghaus
authors.affiliation: Julius Wolff Institute (JWI) and Center for Musculoskeletal Surgery, Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Filter
authors.affiliation: Julius Wolff Institute (JWI) and Center for Musculoskeletal Surgery, Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Rose
authors.affiliation: Center for Musculoskeletal Surgery, Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Preininger
authors.affiliation: Julius Wolff Institute (JWI) and Center for Musculoskeletal Surgery, Charité - University Medicine Berlin, Berlin, Germany.|Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Reinke
authors.affiliation: Julius Wolff Institute (JWI) and Center for Musculoskeletal Surgery, Charité - University Medicine Berlin, Berlin, Germany.|Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Geissler
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité - University Medicine Berlin, Berlin, Germany.|Institute of Medical Immunology, Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Volk
authors.affiliation: Julius Wolff Institute (JWI) and Center for Musculoskeletal Surgery, Charité - University Medicine Berlin, Berlin, Germany.|Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Georg N
authors.initials: GN
authors.lastname: Duda
authors.affiliation: Julius Wolff Institute (JWI) and Center for Musculoskeletal Surgery, Charité - University Medicine Berlin, Berlin, Germany.|Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Dienelt
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001861:Bone Regeneration / Q000276:immunology*; D066026:Endothelial Progenitor Cells / Q000166:cytology / Q000276:immunology* / Q000637:transplantation*; D005260:Female; D006801:Humans; D056747:Immunomodulation; D008297:Male; D008875:Middle Aged; D018919:Neovascularization, Physiologic / Q000276:immunology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D051381:Rats; D017207:Rats, Sprague-Dawley; D033581:Stem Cell Transplantation
chemical_list: D019408:Platelet Endothelial Cell Adhesion Molecule-1
keywords: INJURY/FRACTURE HEALING; OSTEOIMMUNOLOGY; PRECLINICAL STUDIES