14 ASIA PACIFIC BIOTECH NEWS FEATURES Novel Topical Mesenchymal Stem Cell Transplant Paradigm to Treat Organ Diseases by Dr. Ping Kuen Lam, Dr. Kevin K. W. Wang, Dr. Paul BS Lai & Dr. Wai S. Poon Mesenchymal Stem Cells as Organ Treatment Therapy Somatic stem cells attract great scientific and public interest and have real appeal for tissue repair and regeneration. Hematopoietic cells and mesenchymal stem cells are the two major adult stem cells. Mesenchymal Stem Cells (MSCs) were initially found in bone marrow by Friedenstein and his colleagues. Subsequent work showed that MSCs are also present in adipose tissue, placenta, etc. MSCs were characterized as adherent, clonogenic and fibroblastic in appearance. They express CD105, CD73 and CD90 and are negative for CD45, CD34 and CD14. They are a heterogeneous population of multipotent adult stem cells with capacities of prolonged self-renewal and differentiation potential into mature cells of various lineages. Unlike the protocols using embryonic stem cells in regenerative medicine is hindered by ethnical issue and risk of tumor formation, clinical application of autologous MSCs is safe and feasible. In fact, MSCs express human leukocyte antigen (HLA) major histocomplex class (MHC) I and are negative for MHC II and Fas ligand, which enable an allogeneic transplant without immunosuppression. It was initially believed that MSCs differentiated into respective cells of injured tissue, integrated into the disease organ with subsequent restoration of tissue function. More recent data suggest that the therapeutic effects are mediated by paracrine and endocrine actions, resulting in inhibition of inflammation and apoptosis, and also stimulation of mitosis, angiogenesis, proliferation, differentiation of resident tissue-specific precursor stem cells and tissue matrix remodeling. Thus, MSCs have advantages over pharmacological agents that usually target a single pathophysiological cascade of a disease, whereas MSCs work through multiple mechanisms of immunological, inflammatory, vascular and regenerative pathways. The recruitment of MSCs to the injured tissue is the prerequisite for cell therapy. Systemic infusion is the most commonly used administration in animal studies and clinical trials of MSCs. Injured and inflammatory tissues express specific receptors or ligands that facilitate trafficking of MSCs. On the other hand, expression of chemokine and extracellular matrix receptors on the surface of MSCs may account for their homing capacity. It is likely that intravenously infused MSCs preferentially home to the site of injury, probably via SDF1/CXCR4 pathway. However, most of the infused MSCs could be trapped by pulmonary capillaries because of their larger mean diameter. The retention of large amount of MSCs in normal somatic organs may cause unfavorable complications. Delivery of infused MSCs to the brain is further hindered by the blood brain barrier unless it is severely damaged to allow the passage of MSCs. The threat of arterial embolism and occlusion also limit intra-arterial administration of MSCs. Direct injection of MSCs through Hamilton syringe into vascular organs like brain and liver, is associated with high risk of bleeding. A fatality report in the Telegraph newpaper prompted us to revisit the primary consideration of safety when injecting stem cells directly into somatic organs - an 18-month old baby died after receiving a therapeutic intracerebral injection of stem cells [1]. Moreover, repeated trituration of MSC suspension to avoid cell clumps before implantation through Hamilton syringe may inevitably damage the cell membrane, and hence affects cell viability and integration into host tissue. Therefore, an effective and minimally invasive transplantation method is highly desirable. Topical Application of MSCs as a Disruptive Technology Tissue engineering technology is commonly adopted for transplantation of cultured epidermal skin graft to burn wounds and chronic wounds. By borrowing the concept from the tissue engineering technology, we topically applied MSCs which were derived from GFP-transgenic Sprague-Dawley (SD) rats to the surface of somatic organs such as brain, liver, etc. immediately after experimental models of traumatic brain injury (TBI) and hepatic ischemia-reperfusion injury (IRI), respectively [2, 3]. TBI was induced by driving a 3mm diameter tip of an electromagnetically controlled cortical impact device over the exposed parietal cortex of an anesthetized SD rat. On the other hand, IRI was induced by clamping portal vein and hepatic artery for 30 minutes. The MSCs were fixed in a position by a thin layer of fibrin (Baxter). Few days after topical application, immunohistochemistry staining using anti-GFP antibody showed the presence of some GFP-positive cells in the cerebral cortex (Figure 1) and liver parenchyma (Figure 2). These cells expressed the markers of neuron, GFAP and hepatocytes respectively. Compared with the controls (TBI/IRI without any treatment), neurogenesis and liver regeneration were significantly enhanced by the topical MSCs in the respective animals. No GFP-positive cells were found in other organs including the lung. The cellular and molecular