title: Systemic administration of mesenchymal stem cells combined with parathyroid hormone therapy synergistically regenerates multiple rib fractures.
abstract: A devastating condition that leads to trauma-related morbidity, multiple rib fractures, remain a serious unmet clinical need. Systemic administration of mesenchymal stem cells (MSCs) has been shown to regenerate various tissues. We hypothesized that parathyroid hormone (PTH) therapy would enhance MSC homing and differentiation, ultimately leading to bone formation that would bridge rib fractures.
  
  
  
  The combination of human MSCs (hMSCs) and a clinically relevant PTH dose was studied using immunosuppressed rats. Segmental defects were created in animals' fifth and sixth ribs. The rats were divided into four groups: a negative control group, in which animals received vehicle alone; the PTH-only group, in which animals received daily subcutaneous injections of 4 μg/kg teriparatide, a pharmaceutical derivative of PTH; the hMSC-only group, in which each animal received five injections of 2 × 106hMSCs; and the hMSC + PTH group, in which animals received both treatments. Longitudinal in vivo monitoring of bone formation was performed biweekly using micro-computed tomography (μCT), followed by histological analysis.
  
  
  
  Fluorescently-dyed hMSCs were counted using confocal microscopy imaging of histological samples harvested 8 weeks after surgery. PTH significantly augmented the number of hMSCs that homed to the fracture site. Immunofluorescence of osteogenic markers, osteocalcin and bone sialoprotein, showed that PTH induced cell differentiation in both exogenously administered cells and resident cells. μCT scans revealed a significant increase in bone volume only in the hMSC + PTH group, beginning by the 4thweek after surgery. Eight weeks after surgery, 35% of ribs in the hMSC + PTH group had complete bone bridging, whereas there was complete bridging in only 6.25% of ribs (one rib) in the PTH-only group and in none of the ribs in the other groups. Based on the μCT scans, biomechanical analysis using the micro-finite element method demonstrated that the healed ribs were stiffer than intact ribs in torsion, compression, and bending simulations, as expected when examining bone callus composed of woven bone.
  
  
  
  Administration of both hMSCs and PTH worked synergistically in rib fracture healing, suggesting this approach may pave the way to treat multiple rib fractures as well as additional fractures in various anatomical sites.
authors.affiliation: Skeletal Biotech Laboratory, Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem, 91120, Israel.
authors.forename: Doron
authors.initials: D
authors.lastname: Cohn Yakubovich
authors.affiliation: Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.|Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Sheyn
authors.affiliation: Skeletal Biotech Laboratory, Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem, 91120, Israel.
authors.forename: Maxim
authors.initials: M
authors.lastname: Bez
authors.affiliation: Skeletal Biotech Laboratory, Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem, 91120, Israel.
authors.forename: Yeshai
authors.initials: Y
authors.lastname: Schary
authors.affiliation: Skeletal Biotech Laboratory, Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem, 91120, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Yalon
authors.affiliation: Skeletal Biotech Laboratory, Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem, 91120, Israel.
authors.forename: Afeef
authors.initials: A
authors.lastname: Sirhan
authors.affiliation: Skeletal Biotech Laboratory, Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem, 91120, Israel.
authors.forename: May
authors.initials: M
authors.lastname: Amira
authors.affiliation: Skeletal Biotech Laboratory, Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem, 91120, Israel.
authors.forename: Alin
authors.initials: A
authors.lastname: Yaya
authors.affiliation: Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.|Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: De Mel
authors.affiliation: Biomedical Imaging Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Da
authors.affiliation: Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.|Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
authors.forename: Shiran
authors.initials: S
authors.lastname: Ben-David
authors.affiliation: Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.|Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.|Biomedical Imaging Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
authors.forename: Wafa
authors.initials: W
authors.lastname: Tawackoli
authors.affiliation: Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.|Division of Trauma and Critical Care, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Ley
authors.affiliation: Skeletal Biotech Laboratory, Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem, 91120, Israel.|Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.|Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.|Biomedical Imaging Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.|Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Gazit
authors.affiliation: Skeletal Biotech Laboratory, Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem, 91120, Israel. zulma.gazit@csmc.edu.|Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA. zulma.gazit@csmc.edu.|Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA. zulma.gazit@csmc.edu.|Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA. zulma.gazit@csmc.edu.
authors.forename: Zulma
authors.initials: Z
authors.lastname: Gazit
authors.affiliation: Skeletal Biotech Laboratory, Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem, 91120, Israel.|Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.|Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.|Biomedical Imaging Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
authors.forename: Gadi
authors.initials: G
authors.lastname: Pelled
mesh_terms: D000818:Animals; D001861:Bone Regeneration; D004195:Disease Models, Animal; D017102:Fracture Healing / Q000187:drug effects; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000502:physiology; D015675:Osteocalcin / Q000096:biosynthesis; D010281:Parathyroid Hormone / Q000008:administration & dosage*; D051381:Rats; D012253:Rib Fractures / Q000503:physiopathology / Q000628:therapy*; D012795:Sialoglycoproteins / Q000096:biosynthesis; D055114:X-Ray Microtomography
chemical_list: D010281:Parathyroid Hormone; D012795:Sialoglycoproteins; D015675:Osteocalcin
keywords: Parathyroid hormone; Rib fracture; Systemic stem cell administration