Sphingosine-1-Phosphate-Induced Migration and Differentiation of Human Mesenchymal Stem Cells to Smooth Muscle Cells

국문 초록 (Abstract)

중간엽 줄기세포의 이동과 분화는 손상된 조직의 재생을 위해 필수적이다. Sphingosine-1-phosphate (S1P)는 세포성장, 생존, 분화, 이동성 등 여러 가지 생명현상에 중요한 역할을 하는 생리활성 지질이다. 본 연구에서는 인체 골수유래 중간엽 줄기세포의 이동과 세포분화에 대한 S1P의 영향을 조사하였다. S1P는 중간엽 줄기세포의 이동을 증가시켰으며 pertussis toxin의 전처리는 S1P에 의한 세포이동을 억제하였다. 본 결과는 S1P에 의한 세포이동과정에 Gi에 연결된 수용체가 관여함을 제시한다. S1P₁과 S1P₃ 수용체에 대한 길항제인 VPC23019의 전처리나 siRNA를 이용한 S1P₁ 수용체의 발현억제는 S1P에 의한 세포 내 칼슘 증가와 중간엽 줄기세포의 이동을 저해하였다. 또한, S1P의 처리는 중간엽 줄기세포에서 평활근세포의 표지유전자인 α-smooth muscle actin (α-SMA)의 발현을 증가시켰으며 VPC23019의 전처리는 S1P에 의한 α-SMA의 발현증가를 저해하였다. S1P는 중간엽 줄기세포에서 p38 mitogen-activated protein kinase (p38 MAPK)의 인산화를 촉진하였으며 p38 MAPK의 저해제인 SB202190의 전처리 또는 p38 MAPK의 dominant negative mutant의 과발현은 S1P에 의한 중간엽 줄기세포의 이동 α-SMA 발현증가를 억제하였다. 본 연구결과는 S1P가 S1P1-p38 MAPK 신호전달기전을 통해 중간엽 줄기세포의 이동과 평활근세포로의 분화를 촉진함으로써 중간엽 줄기세포를 이용한 조직재생에의 활용 가능성을 제시한다.

다국어 초록 (Multilingual Abstract)

Migration and differentiation of mesenchymal stem cells are crucial for tissue regeneration in response to injury. Sphingosine-1-phosphate (S1P) is a bioactive lipid that regulates a variety of biological processes, including proliferation, survival, differentiation and motility. In the present study, we determined the role of S1P in migration and differentiation of human bone marrow-derived mesenchymal stem cells (BMSCs). S1P stimulated migration of BMSCs in a dose- and time-dependent manner, and pre-incubation of the cells with pertussis toxin completely abrogated S1P-induced migration, suggesting involvement of Gi-coupled receptors in S1P-induced cell migration. S1P elicited elevation of intracellular concentration of Ca<SUP>2+</SUP> ([Ca<SUP>2+</SUP>]i) and pretreatment with VPC23019, an antagonist of S1P₁/S1P₃, blocked S1P-induced migration and increase of [Ca<SUP>2+</SUP>]i. Small interfering RNA-mediated knockdown of endogenous S1P1 attenuated S1P-induced migration of BMSCs. Furthermore, S1P treatment induced expression of α-smooth muscle actin (α-SMA), a smooth muscle marker, and pretreatment with VPC23019 abrogated S1P-induced α-SMA expression. S1P induced phosphorylation of p38 mitogen-activated protein kinase (MAPK), and pretreatment of cells with SB202190, an inhibitor of p38 MAPK, or adenoviral overexpression of a dominant-negative mutant of the p38 MAPK blocked S1P-induced cell migration and α-SMA expression. Taken together, these results suggest that S1P stimulates migration and smooth muscle differentiation of BMSCs through an S1P1-p38 MAPK-dependent mechanism.

목차 (Table of Contents)

• Introduction
• Materials and Methods
• Results
• Discussion
• Acknowledgement
• References
• 초록

참고문헌 (Reference)

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