Publication of the Month 2006

Title: Cartilage repair using bone morphogenetic protein 4 and muscle-derived stem cells

Summary: Objective: Muscle-derived stem cells (MDSCs) isolated from mouse skeletal muscle exhibit long-time proliferation, high self-renewal, and multipotent differentiation. This study was undertaken to investigate the ability of MDSCs that were retrovirally transduced to express bone morphogenetic protein 4 (BMP-4) to differentiate into chondrocytes in vitro and in vivo and enhance articular cartilage repair. Methods: Using monolayer and micromass pellet culture systems, we evaluated the in vitro chondrogenic differentiation of LacZ- and BMP-4-transduced MDSCs with or without transforming growth factor 1 (TGF1) stimulation. We used a nude rat model of a full-thickness articular cartilage defect to assess the duration of LacZ transgene expression and evaluate the ability of transplanted cells to acquire a chondrocytic phenotype. We evaluated cartilage repair macroscopically and histologically 4, 8, 12, and 24 weeks after surgery, and performed histologic grading of the repaired tissues. Results: BMP-4-expressing MDSCs acquired a chondrocytic phenotype in vitro more effectively than did MDSCs expressing only LacZ; the addition of TGF1 did not alter chondrogenic differentiation of the BMP-4-transduced MDSCs. LacZ expression within the repaired tissue continued for up to 12 weeks. Four weeks after surgery, we detected donor cells that coexpressed -galactosidase and type II collagen. Histologic scoring of the defect sites 24 weeks after transplantation revealed significantly better cartilage repair in animals that received BMP-4-transduced MDSCs than in those that received MDSCs expressing only LacZ. Conclusion: Local delivery of BMP-4 by genetically engineered MDSCs enhanced chondrogenesis and significantly improved articular cartilage repair in rats.

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1-Center for Regenerative Biology and Department of Animal Science, University of Connecticut, Storrs, Connecticut 06269, USA.
2-Cancer Stem Cell Program, University of Pittsburgh Cancer Institute and Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
3-Department of Statistics, University of Connecticut, Storrs, Connecticut 06269, USA.
4-Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
5-Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
6-These authors contributed equally to this work.

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Pittsburgh NMR Center for Biomedical Research, Department of Biological Sciences, Carnegie Mellon University

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From the Departments of Pathology,* Medicine (Gastroenterology), and Surgery and Bioengineering, McGowan Institute for Regenerative Medicine, and the Department of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania; and the Department of Surgery,¶ Charité-Campus Virchow, Humboldt University, Berlin, Germany

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Title: Modeling the interactions between deformable capsules rolling on a compliant surface

Summary: By integrating mesoscale models for hydrodynamics and micromechanics, we examine the fluid-driven motion of pairs of capsules on a compliant, adhesive substrate. The capsules, modeled as fluid filled elastic shells, represent ex vivo cells or polymeric microcapsules. We show that both the relative and the average velocities of two closely spaced, rolling capsules depends on the elasticity of the capsules, the adhesive interaction between the capsules and the substrate, and the compliance of the substrate. We first focused on a stiff surface and found that pairs of rigid capsules always separate from each other, while for deformable capsules, the dynamic behavior depends critically on the strength of the adhesive interaction. For strong adhesion to the substrate, the capsules again roll away from each other, while for a relatively weak adhesion, the capsules actually approach each other. In the case of soft substrates, any significant deformations of the surface that are caused by the capsules give rise to a force that propels the particles to move rapidly apart. Thus, in the case of strong adhesion between the capsules and the soft substrates, both rigid and flexible capsules are driven to separate. On the other hand, for weak adhesion, the elastic particles approach each other, similar to the behavior on stiff surfaces. These findings reveal that the interactions between the capsules are mediated by the nature of the underlying layer. We can harness this information to design surfaces that actively control the relative separation between the capsules. This could be utilized to regulate the motion of biological cells, as well as polymeric microcapsules, and thus, could prove to be useful in various biological assays or tissue engineering studies.

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From the Departments of Surgery (P.V.K., I.B.K., G.R.G.) and Biomedical Engineering (E.U.A., D.J.K., I.B.K., G.R.G.), Stony Brook University, Stony Brook, New York; the McGowan Institute for Regenerative Medicine (S.F.B.), Pittsburgh, Pa; the Institute of Molecular Cardiology (S.V.D., I.B.K., I.S.C., G.R.G.), Stony Brook, New York; and the Department of Surgery (G.R.G.), University of Massachusetts Medical School, Worcester, Mass.

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Title: Design and analysis of tissue engineering scaffolds that mimic soft tissue mechanical anisotropy

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a) Inserm U506, Hopital Paul Brousse, Villejuif, France

b) Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA

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1) Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
2) Center for Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA, USA
3) Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
4) Neurology Clinical Trials Unit, Massachusetts General Hospital East, Charlestown, MA, USA
5) Day Neuromuscular Research Laboratory, Massachusetts General Hospital East, Charlestown, MA, USA

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Title: Differential Myocardial Infarct Repair with Muscle Stem Cells Compared to Myoblasts

Summary: Myoblast transplantation for cardiac repair has generated beneficial results in both animals and humans; however, poor viability and poor engraftment of myoblasts after implantation in vivo limit their regeneration capacity. We and others have identified and isolated a subpopulation of skeletal muscle-derived stem cells (MDSCs) that regenerate skeletal muscle more effectively than myoblasts.

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Title: Surgical treatment for congestive heart failure with autologous adult stem cell transplantation: A prospective randomized study.

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