title: Human mesenchymal stem cell-derived matrices for enhanced osteoregeneration.
abstract: The methodology for the repair of critical-sized or non-union bone lesions has unpredictable efficacy due in part to our incomplete knowledge of bone repair and the biocompatibility of bone substitutes. Although human mesenchymal stem cells (hMSCs) differentiate into osteoblasts, which promote bone growth, their ability to repair bone in vivo has been variable. We hypothesized that given the multistage process of osteogenesis, hMSC-mediated repair might be maximal at a specific time point of healing. Using a mouse model of calvarial healing, we demonstrate that the osteo-repair capacity of hMSCs can be substantially augmented by treatment with an inhibitor of peroxisome proliferator-activated receptor γ, but efficacy is confined to the rapid osteogenic phase. Upon entry into the bone-remodeling phase, hMSC retention signals are lost, resulting in truncation of healing. To solve this limitation, we prepared a scaffold consisting of hMSC-derived extracellular matrix (ECM) containing the necessary biomolecules for extended site-specific hMSC retention. When inhibitor-treated hMSCs were coadministered with ECM, they remained at the injury, well into the remodeling phase of healing, which resulted in reproducible and complete repair of critical-sized bone defects in mice in 3 weeks. These data suggest that hMSC-derived ECM and inhibitor-treated hMSCs could be used at optimal times to substantially and reproducibly improve bone repair.
authors.affiliation: Institute for Regenerative Medicine at Scott and White Hospital, Texas A&M Health Science Center, Module C, 5701 Airport Road, Temple, TX 76502, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Zeitouni
authors.forename: Ulf
authors.initials: U
authors.lastname: Krause
authors.forename: Bret H
authors.initials: BH
authors.lastname: Clough
authors.forename: Hillary
authors.initials: H
authors.lastname: Halderman
authors.forename: Alexander
authors.initials: A
authors.lastname: Falster
authors.forename: Darryl T
authors.initials: DT
authors.lastname: Blalock
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Chaput
authors.forename: H Wayne
authors.initials: HW
authors.lastname: Sampson
authors.forename: Carl A
authors.initials: CA
authors.lastname: Gregory
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001861:Bone Regeneration / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D012886:Skull / Q000187:drug effects / Q000473:pathology; D013997:Time Factors; D014945:Wound Healing / Q000187:drug effects
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D003094:Collagen; D000469:Alkaline Phosphatase