CIRCULATING MESENCHYMAL STEM CELLS AND THEIR CLINICAL IMPLICATIONS

Abstract

Introduction: MSCs were demonstrated to exist within peripheral blood (PB) of several mammalian species including human, guinea pig, mice, rat, and rabbit. We have found increased numbers of circulating MSCs in human peripheral blood after fracture and in patients with cancers. We have also compared the difference between circulating MSCs and bone marrow MSCs and evaluated their potential clinical applications in tissue engineering and cell therapy.

Methods and findings: Using culture conditions similar to those defined for bone marrow derived mesenchymal stromal cells (BMMSCs), we have isolated and expanded multi-colony and single colony derived PBMSCs strains from the GFP transgenic rats. Aspects of molecular, cellular and developmental properties of this poorly characterized peripheral blood subpopulation were examined. PBMSCs share some common phenotypic characteristics with BMMSCs, but are distinguishable in gene expression profile by cDNA microarray analysis, with 84 up-regulated and 83 down-regulated genes (> 2 fold, E-B/B-E> 100, P< 0.05). Most of these genes are related to cell proliferation, differentiation, cyto-skeleton, and calcium/iron homeostasis. Differentially expressed genes with fold change ≥10 were further confirmed with quantitative real time RT-PCR, and these genes are: retinol-binding protein 1 (CRBP1), cadherin 2, bone morphogenetic protein 6 (BMP6), SRY-box containing gene 11 (Sox11), the aquaporin 1 (AQP1), and so on, and they can be potential targets for further investigations. We have demonstrated that single colony derived PBMSCs strains possess extensive proliferation and multipotent differentiation potentials into osteoblasts, adipocytes, chondrocytes, endothelial cells and neuronal cells. In terms of potential clinical implications of PBMSCs, we have demonstrated that allogenic PB-MSCs enhance bone regeneration in rabbit ulna critical-sized bone defect model. We also demonstrated that BM-MSCs can be recruited towards to the sites of bone fracture and participate fracture healing. We are now working on using MSCs as a gene delivery vehicle for management of would healing or cancer therapy, and ways of enhancing the homing and recruitment MSCs towards to specific sites after their systemic delivery.

Conclusion: Taken the above data together, PB-MSCs may be a new cell source for cell therapy, tissue engineering and gene therapy strategies.