human mesenchymal stem cells self-renew and differentiate according to a deterministic hierarchy人类间充质干细胞自我更新和分化根据确定的层次结构.pdfVIP

Human Mesenchymal Stem Cells Self-Renew and Differentiate According to a Deterministic Hierarchy 1 1 1,2 1 1 Rahul Sarugaser , Lorraine Hanoun , Armand Keating , William L. Stanford , John E. Davies * 1 Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada, 2 Princess Margaret Hospital, Toronto, Ontario, Canada Abstract Background: Mesenchymal progenitor cells (MPCs) have been isolated from a variety of connective tissues, and are commonly called ‘‘mesenchymal stem cells’’ (MSCs). A stem cell is defined as having robust clonal self-renewal and multilineage differentiation potential. Accordingly, the term ‘‘MSC’’ has been criticised, as there is little data demonstrating self-renewal of definitive single-cell-derived (SCD) clonal populations from a mesenchymal cell source. Methodology/Principal Findings: Here we show that a tractable MPC population, human umbilical cord perivascular cells (HUCPVCs), was capable of multilineage differentiation in vitro and, more importantly, contributed to rapid connective tissue healing in vivo by producing bone, cartilage and fibrous stroma. Furthermore, HUCPVCs exhibit a high clonogenic frequency, allowing us to isolate definitive SCD parent and daughter clones from mixed gender suspensions as determined by Y-chromosome fluorescent in situ hybridization. Conclusions/Significance: Analysis of the multilineage differentiation capacity of SCD parent clones and daughter clones enabled us to formulate a new hierarchical schema for MSC self-renewal and differentiation in which a self-renewing multipotent MSC gives rise to more restricted self-renewing progenitor