TY - JOUR
T1 - Promotion of hydroxyapatite-associated, stem cell-based bone regeneration by CCN2
AU - Ono, Mitsuaki
AU - Kubota, Satoshi
AU - Fujisawa, Takuo
AU - Sonoyama, Wataru
AU - Kawaki, Harumi
AU - Akiyama, Kentaro
AU - Shimono, Kengo
AU - Oshima, Masamitsu
AU - Nishida, Takashi
AU - Yoshida, Yasuhiro
AU - Suzuki, Kazuomi
AU - Takigawa, Masaharu
AU - Kuboki, Takuo
PY - 2008
Y1 - 2008
N2 - Multiple roles have been already recognized for CCN2 in cartilage development and regeneration. However, the effects of CCN2 on bone regeneration remain to be elucidated. In this study, the utility of CCN2 on bone regeneration was examined in vitro and in vivo in combination with hydroxyapatite (HAp) as a scaffold. Human bone marrow stromal cells (hBMSCs) were isolated from human iliac bone marrow aspirates of healthy donors and expanded, and the effects of CCN2 on their proliferation and migration were examined in vitro. The proliferation of hBMSCs on a plastic or HAp plate was significantly enhanced by CCN2. Moreover, the migration of hBMSCs also dramatically increased by CCN2. Interestingly, a C-terminal signal modular fragment of CCN2 (CT-module) also enhanced the cell proliferation and migration as efficiently as the full-length CCN2. Next, in order to estimate the effect of CCN2 on the migration and survival of hBMSCs and bone formation inside the HAp scaffold in vivo, two experiments were performed. First, the porous HAp carrier was cultured with hBMSCs for a week, and the cell-scaffold hybrid was transplanted with or without CCN2 subcutaneously into immunocompromised mice. CCN2 accelerated the hBMSC-like cell migration and survival inside the porous HAp within 4 weeks after transplantation. Second, the porous HAp carrier with or without CCN2 was directly implanted into bone defects within a rabbit mandible, and bone regeneration inside was evaluated. As a result, CCN2 efficiently induced the cell invasion and bone formation inside the porous HAp scaffold. These findings suggest that CCN2 and its CT-module fragment could be useful for regeneration and reconstruction of large-scale bone defects.
AB - Multiple roles have been already recognized for CCN2 in cartilage development and regeneration. However, the effects of CCN2 on bone regeneration remain to be elucidated. In this study, the utility of CCN2 on bone regeneration was examined in vitro and in vivo in combination with hydroxyapatite (HAp) as a scaffold. Human bone marrow stromal cells (hBMSCs) were isolated from human iliac bone marrow aspirates of healthy donors and expanded, and the effects of CCN2 on their proliferation and migration were examined in vitro. The proliferation of hBMSCs on a plastic or HAp plate was significantly enhanced by CCN2. Moreover, the migration of hBMSCs also dramatically increased by CCN2. Interestingly, a C-terminal signal modular fragment of CCN2 (CT-module) also enhanced the cell proliferation and migration as efficiently as the full-length CCN2. Next, in order to estimate the effect of CCN2 on the migration and survival of hBMSCs and bone formation inside the HAp scaffold in vivo, two experiments were performed. First, the porous HAp carrier was cultured with hBMSCs for a week, and the cell-scaffold hybrid was transplanted with or without CCN2 subcutaneously into immunocompromised mice. CCN2 accelerated the hBMSC-like cell migration and survival inside the porous HAp within 4 weeks after transplantation. Second, the porous HAp carrier with or without CCN2 was directly implanted into bone defects within a rabbit mandible, and bone regeneration inside was evaluated. As a result, CCN2 efficiently induced the cell invasion and bone formation inside the porous HAp scaffold. These findings suggest that CCN2 and its CT-module fragment could be useful for regeneration and reconstruction of large-scale bone defects.
KW - Bone marrow stromal cell
KW - Bone regeneration
KW - CCN2/connective tissue growth factor
KW - Hydroxyapatite
KW - Mesenchymal stem cell
UR - http://www.scopus.com/inward/record.url?scp=42249114016&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=42249114016&partnerID=8YFLogxK
U2 - 10.3727/000000008783907143
DO - 10.3727/000000008783907143
M3 - Article
C2 - 18468254
AN - SCOPUS:42249114016
VL - 17
SP - 231
EP - 240
JO - Cell Transplantation
JF - Cell Transplantation
SN - 0963-6897
IS - 1-2
ER -