title: FTY720 promotes local microvascular network formation and regeneration of cranial bone defects.
abstract: The calvarial bone microenvironment contains a unique progenitor niche that should be considered for therapeutic manipulation when designing regeneration strategies. Recently, our group demonstrated that cells isolated from the dura are multipotent and exhibit expansion potential and robust mineralization on biodegradable constructs in vitro. In this study, we evaluate the effectiveness of healing critical-sized cranial bone defects by enhancing microvascular network growth and host dura progenitor trafficking to the defect space pharmacologically by delivering drugs targeted to sphingosine 1-phosphate (S1P) receptors. We demonstrate that delivery of pharmacological agonists to (S1P) receptors S1P(1) and S1P(3) significantly increase bone ingrowth, total microvessel density, and smooth muscle cell investment on nascent microvessels within the defect space. Further, in vitro proliferation and migration studies suggest that selective activation of S1P(3) promotes recruitment and growth of osteoblastic progenitors from the meningeal dura mater.
authors.affiliation: Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Caren E
authors.initials: CE
authors.lastname: Petrie Aronin
authors.forename: Lauren S
authors.initials: LS
authors.lastname: Sefcik
authors.forename: Sunil S
authors.initials: SS
authors.lastname: Tholpady
authors.forename: Ashok
authors.initials: A
authors.lastname: Tholpady
authors.forename: Karim W
authors.initials: KW
authors.lastname: Sadik
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Macdonald
authors.forename: Shayn M
authors.initials: SM
authors.lastname: Peirce
authors.forename: Brian R
authors.initials: BR
authors.lastname: Wamhoff
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Lynch
authors.forename: Roy C
authors.initials: RC
authors.lastname: Ogle
authors.forename: Edward A
authors.initials: EA
authors.lastname: Botchwey
mesh_terms: D000818:Animals; D001847:Bone Diseases / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000601:surgery*; D001861:Bone Regeneration / Q000187:drug effects*; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D055806:Microvessels / Q000000981:diagnostic imaging / Q000187:drug effects*; D011409:Propylene Glycols / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D049349:Receptors, Lysosphingolipid / Q000819:agonists; D012886:Skull / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology / Q000601:surgery*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D054457:Tissue Scaffolds / Q000737:chemistry*; D055114:X-Ray Microtomography
chemical_list: D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine