Stimulate Tissue Repair Research Articles

Human Placenta Extract Could Promote Proliferating Cell Nuclear Antigen Expression during Liver Regeneration Induced by Partial Hepatectomy in Rats

Human placenta extract (hPE) has therapeutic potential against certain diseases such as burn injury, liver cirrhosis and chronic wound through stimulating tissue repair processes. However, the effects of hPE on liver regeneration in animals are unknown. This study investigated the effect of hPE on the expression of proliferating cell nuclear antigen (PCNA) during liver regeneration induced by partial hepatectomy (PH) in rats. The activities of AST, ALT and ALP increased during a few days after PH. A high level of ALP was particularly seen at day 3 in the control group. All the levels of experimental groups were normalized by day 5 after PH. On immunohistochemistry, the expression of PCNA increased at the early days, showed a peak at day 3 after PH. The PCNA staining was more obvious in the experimental group over the whole period. By western blotting, PCNA seemed to be more strongly expressed in the hPE injected group in the early stage and fell to almost undetectable levels at day 7. On immunocytochemical observations, the number of PCNA-gold particles in the nuclei at day 1 of the hPE treated groups was more than those of the untreated groups. The results suggest that hPE could accelerate liver regeneration induced by PH involving the expression of PCNA in rats.

Adipose stem cells can secrete angiogenic factors that inhibit hyaline cartilage regeneration

IntroductionAdipose stem cells (ASCs) secrete many trophic factors that can stimulate tissue repair, including angiogenic factors, but little is known about how ASCs and their secreted factors influence cartilage regeneration. Therefore, the aim of this study was to determine the effects ASC-secreted factors have in repairing chondral defects.MethodsASCs isolated from male Sprague Dawley rats were cultured in monolayer or alginate microbeads supplemented with growth (GM) or chondrogenic medium (CM). Subsequent co-culture, conditioned media, and in vivo cartilage defect studies were performed.ResultsASC monolayers and microbeads cultured in CM had decreased FGF-2 gene expression and VEGF-A secretion compared to ASCs cultured in GM. Chondrocytes co-cultured with GM-cultured ASCs for 7 days had decreased mRNAs for col2, comp, and runx2. Chondrocytes treated for 12 or 24 hours with conditioned medium from GM-cultured ASCs had reduced sox9, acan, and col2 mRNAs; reduced proliferation and proteoglycan synthesis; and increased apoptosis. ASC-conditioned medium also increased endothelial cell tube lengthening whereas conditioned medium from CM-cultured ASCs had no effect. Treating ASCs with CM reduced or abolished these deleterious effects while adding a neutralizing antibody for VEGF-A eliminated ASC-conditioned medium induced chondrocyte apoptosis and restored proteoglycan synthesis. FGF-2 also mitigated the deleterious effects VEGF-A had on chondrocyte apoptosis and phenotype. When GM-grown ASC pellets were implanted in 1 mm non-critical hyaline cartilage defects in vivo, cartilage regeneration was inhibited as evaluated by radiographic and equilibrium partitioning of an ionic contrast agent via microCT imaging. Histology revealed that defects with GM-cultured ASCs had no tissue ingrowth from the edges of the defect whereas empty defects and defects with CM-grown ASCs had similar amounts of neocartilage formation.ConclusionsASCs must be treated to reduce the secretion of VEGF-A and other factors that inhibit cartilage regeneration, which can significantly influence how ASCs are used for repairing hyaline cartilage.

Targeting the Hepatocyte Growth Factor–cMET Axis in Cancer Therapy

The hepatocyte growth factor (HGF) and its receptor, the transmembrane tyrosine kinase cMET, promote cell proliferation, survival, motility, and invasion as well as morphogenic changes that stimulate tissue repair and regeneration in normal cells but can be co-opted during tumor growth. MET overexpression, with or without gene amplification, has been reported in a variety of human cancers, including breast, lung, and GI malignancies. Furthermore, high levels of HGF and/or cMET correlate with poor prognosis in several tumor types, including breast, ovarian, cervical, gastric, head and neck, and non-small-cell lung cancers. Gene amplification and protein overexpression of cMET drive resistance to epidermal growth factor receptor family inhibitors, both in preclinical models and in patients. It is increasingly apparent that the HGF-cMET axis signaling network is complex, and rational combinatorial therapy is needed for optimal clinical efficacy. Better understanding of HGF-cMET axis signaling and the mechanism of action of HGF-cMET inhibitors, along with the identification of biomarkers of response and resistance, will lead to more effective targeting of this pathway for cancer therapy.

Incorporating Platelet-Rich Plasma into Electrospun Scaffolds for Tissue Engineering Applications

Platelet-rich plasma (PRP) therapy has seen a recent spike in clinical interest due to the potential that the highly concentrated platelet solutions hold for stimulating tissue repair and regeneration. The aim of this study was to incorporate PRP into a number of electrospun materials to determine how growth factors are eluted from the structures, and what effect the presence of these factors has on enhancing electrospun scaffold bioactivity. PRP underwent a freeze-thaw-freeze process to lyse platelets, followed by lyophilization to create a powdered preparation rich in growth factors (PRGF), which was subsequently added to the electrospinning process. Release of protein from scaffolds over time was quantified, along with the quantification of human macrophage and adipose-derived stem cell (ADSC) chemotaxis and proliferation. Protein assays demonstrated a sustained release of protein from PRGF-containing scaffolds at up to 35 days in culture. Scaffold bioactivity was enhanced as ADSCs demonstrated increased proliferation in the presence of PRGF, whereas macrophages demonstrated increased chemotaxis to PRGF. In conclusion, the work performed in this study demonstrated that the incorporation of PRGF into electrospun structures has a significant positive influence on the bioactivity of the scaffolds, and may prove beneficial in a number of tissue engineering applications.

Synthesis and biological activities of a library of glycosaminoglycans mimetic oligosaccharides

Biologically active oligosaccharides related to glycosaminoglycans are accumulating increased attention because of their therapeutic potential and for their value in mechanistic studies. Heparan mimetics (HMs) are a family of dextran based polymer known to mimic the properties of glycosaminoglycans, and particularly those of heparan sulfates, as to interact with heparin binding proteins. HMs have shown to stimulate tissue repair in various animal models. Here, we use different methods to depolymerize HMs in order to produce a library of related oligosaccharides and study their biological activities. Since HMs were resistant to endoglycanases activities, depolymerization was achieved by chemical approaches. In vitro biological studies showed that HM oligosaccharides can differentially potentiate FGF-2 mitogenic and antithrombotic activities. In vivo, a selected oligosaccharide (H-dp12) showed to be able to regenerate tissue almost as well as the related polymeric product. The very low anticoagulant activity and high biological activity of low mass oligosaccharides give to these products a new therapeutic potential.

Mesenchymal stem cells: a new therapeutic tool for AKI

Acute kidney injury (AKI) is a common clinical complication, associated with poor outcomes and the development of chronic kidney disease. Despite major advances in the understanding of its pathophysiology, available therapies for AKI are only supportive; therefore, adequate functional recovery from AKI must predominantly rely on the kidney's own reparative ability. An extensive body of preclinical data from our own and from other laboratories has shown that administration of adult multipotent marrow stromal cells (commonly referred to as mesenchymal stem cells [MSCs]), effectively ameliorates experimental AKI by exerting paracrine renoprotective effects and by stimulating tissue repair. Based on these findings, a clinical trial has been conducted to investigate the safety and efficacy of MSCs administered to open-heart surgery patients who are at high risk of postoperative AKI. In this Perspectives article, we discuss some of the early data from this trial and describe potential applications for stem cell therapies in other fields of nephrology.

Glycosaminoglycan mimetics trigger IP3-dependent intracellular calcium release in myoblasts

Glycosaminoglycans (GAG) are sulfated polysaccharides that play an important role in regulating cell functions. GAG mimetics called RGTAs (for ReGeneraTing Agents) have been shown to stimulate tissue repair. In particular they accelerate myogenesis, in part via their heparin-mimetic property towards growth factors. RGTAs also increase activity of calcium-dependent intracellular protease suggesting an effect on calcium cellular homeostasis. This effect was presently investigated on myoblasts in vitro using one member of the RGTA family molecule named OTR4120. We have shown that OTR4120 or heparin induced transient increases of intracellular calcium concentration ([Ca2+]i) in pre-fusing myoblasts from both mouse SolD7 cell line and rat skeletal muscle satellite cells grown in primary culture by mobilising sarcoplasmic reticulum store. This [Ca2+]i was not mediated by ryanodine receptors but instead resulted from stimulation of the Inositol-3 phosphate-phospholipase C activation pathway. OTR4120-induced calcium transient was not mediated through an ATP, nor a tyrosine kinase, nor an acetylcholine receptor but principally through serotonin 5-HT2A receptor. This original finding shows that the GAG mimetic can induce calcium signal through serotonin receptors and the IP3 pathway may be relevant to its ability to favour myoblast differentiation. It supports a novel and unexpected function of GAGs in the regulation of calcium homeostasis.

Mechanotherapy: how physical therapists’ prescription of exercise promotes tissue repair

Mechanotransduction is the physiological process where cells sense and respond to mechanical loads. This paper reclaims the term “mechanotherapy” and presents the current scientific knowledge underpinning how load may be...

Pathobiology of Inflammation to Cell Death

When a cell dies in vivo the innate immune system investigates the scene of the crime. If the death of the cell is physiological, e.g. as part of normal cell turn over, then the corpse is cleared and little else is done. In fact, as part of this process phagocytes that ingest normal apoptotic cells can actively suppress tissue responses by elaborating anti-inflammatory cytokines (1). However, if the cell has died unexpectedly from some pathological process, then the innate immune system expands its investigation.

Solid emulsion gel as a vehicle for delivery of polyunsaturated fatty acids: implications for tissue repair, dermal angiogenesis and wound healing

The paper describes preparation and biological characterization of the solid hybrid biomaterial that was designed for cell-targeted lipid delivery in healing tissues. The material referred to as 'solid emulsion gel' combines a protein-stabilized lipid emulsion and a hydrogel structure in a single compartment. The potential of the omega-3 (n-3)-fatty acids rich solid emulsion gel for tissue repair applications was investigated at the macro-, micro-, molecular and gene expression levels, using human fibroblasts and endothelial cells and a porcine model of full-thickness wounds. Being non-cytotoxic in vitro and in vivo, the biomaterial was found to affect cell metabolism, modulate expression of certain genes, stimulate early angiogenesis and promote wound repair in vivo. The neovascular response in vivo was correlated with upregulated expression of the genes involved in lipid transport (e.g. adipophilin), anti-apoptosis (e.g. heat shock proteins, haem oxygenase 1) and angiogenesis (vascular endothelial growth factor, placental growth factor). Collectively, the results of this study provide first evidence that the angiogenic response provided by solid emulsion gel-mediated delivery of n-3 fatty acids is an alternative to the topical administration of exogenous growth factors or gene therapy, and can be advantageously used for the stimulation of tissue repair in complex wounds.

Effect of Platelet‐Rich Plasma on Cell Adhesion, Cell Migration, and Myofibroblastic Differentiation in Human Gingival Fibroblasts

Platelet-rich plasma is a blood-derived fraction that contains a high concentration of platelets and growth factors. It was proposed that the use of this platelet concentrate stimulates tissue repair. However, little is known about the biologic response of gingival fibroblasts to platelet's derived growth factors. In the present study, we evaluated whether platelet-rich plasma modulated cell adhesion, cell migration, and myofibroblastic differentiation in primary cultures of human gingival fibroblasts. We studied the response of primary cultures of gingival fibroblasts to thrombin-activated platelet-rich plasma fractions. Cell adhesion was evaluated through a colorimetric assay. Cell spreading, actin cytoskeleton remodeling, and focal adhesion distribution were assessed through light and immunofluorescence microscopy. Cell migration was analyzed using a bicameral cell culture system. Smooth muscle actin production was studied through Western blotting. Exposure of gingival fibroblasts to platelet-rich plasma stimulated adhesion and spreading of cells on fibronectin matrices, the development of actin-enriched cellular extensions, and formation of focal adhesions. Platelet-rich plasma also promoted cell migration and invasion through a reconstituted basement membrane matrix. Differentiation into the myofibroblastic phenotype, assessed through the production of smooth muscle actin, was also stimulated by platelet-rich plasma preparations. Platelet-rich plasma may modulate several cell responses potentially involved in wound healing such as cell adhesion, cell migration, and myofibroblastic differentiation.

High-Mobility Group Box 1 Activates Integrin-Dependent Homing of Endothelial Progenitor Cells

Endothelial progenitor cells (EPCs) are recruited to ischemic regions and improve neovascularization. Integrins contribute to EPC homing. High-mobility group box 1 (HMGB1) is a nuclear protein that is released extracellularly on cell necrosis and tissue damage, eliciting a proinflammatory response and stimulating tissue repair. In the present study, we investigated the effects of HMGB1 on EPC homing. EPCs express the HMGB1 receptors RAGE (receptor for advanced glycation end products) and TLR2 (Toll-like receptor 2). EPC migration was stimulated by HMGB1 in a RAGE-dependent manner. In addition, the HMGB1-induced migration of EPCs on fibronectin and fibrinogen was significantly inhibited by antibodies against beta1 and beta2 integrins, respectively. Short-term prestimulation of EPCs with HMGB1 also increased EPC adhesion to endothelial cell monolayers, and this effect was blocked by antibodies to beta2 integrins or RAGE. HMGB1 increased EPC adhesion to the immobilized integrin ligands intercellular adhesion molecule-1 and fibronectin in a RAGE-dependent manner. Strikingly, HMGB1 rapidly increased integrin affinity and induced integrin polarization. Using intravital microscopy in a tumor model of neovascularization, prestimulation of EPCs with HMGB1 enhanced the initial in vivo adhesion of EPCs to microvessels and the recruitment of EPCs in the tumor tissue. In addition, prestimulation of EPCs with HMGB1 increased the homing of EPCs to ischemic muscles. In conclusion, these data represent a link between HMGB1 and integrin functions of EPCs and demonstrate that HMGB1 stimulates EPC homing to ischemic tissues. These results may provide a platform for the development of novel therapeutic approaches to improve EPC homing.

Prior administration of a low dose of thioacetamide protects type 1 diabetic rats from subsequent administration of lethal dose of thioacetamide

Previously, we reported that an ordinarily non-lethal dose of thioacetamide (TA, 300 mg/kg) causes 90% mortality in type 1 diabetic rats due to inhibited liver tissue repair, whereas 30 mg TA/kg allows 100% survival due to stimulated although delayed tissue repair. Objective of this investigation was to test whether prior administration of a low dose of TA (30 mg/kg) would lead to sustainable stimulation of liver tissue repair in type 1 diabetic rats sufficient to protect from a subsequently administered lethal dose of TA. Therefore, in the present study, the hypothesis that preplacement of tissue repair by a low dose of TA (30 mg TA/kg, ip) can reverse the hepatotoxicant sensitivity (autoprotection) in type 1 diabetic rats was tested. Preliminary studies revealed that a single intraperitoneal (ip) administration of TA causes 90% mortality in diabetic rats with as low as 75 mg/kg. To establish an autoprotection model in diabetic condition, diabetic rats were treated with 30 mg TA/kg (priming dose). Administration of priming dose stimulated tissue repair that peaked at 72 h, at which time these rats were treated with a single ip dose of 75 mg TA/kg. Our results show that tissue repair stimulated by the priming dose enabled diabetic rats to overexpress, calpastatin, endogenous inhibitor of calpain, to inhibit calpain-mediated progression of liver injury induced by the subsequent administration of lethal dose, resulting in 100% survival. Further investigation revealed that protection observed in these rats is not due to decreased bioactivation. These studies underscore the importance of stimulation of tissue repair in the final outcome of liver injury (survival/death) after hepatotoxicant challenge. Furthermore, these results also suggest that it is possible to stimulate tissue repair in diabetics to overcome the enhanced sensitivity of hepatotoxicants.

A Synthetic Glycosaminoglycan Mimetic Binds Vascular Endothelial Growth Factor and Modulates Angiogenesis

In a previous study, we showed that in situ injection of glycosaminoglycan mimetics called RGTAs (ReGeneraTing Agents) enhanced neovascularization after skeletal muscular ischemia (Desgranges, P., Barbaud, C., Caruelle, J. P., Barritault, D., and Gautron, J. (1999) FASEB J. 13, 761-766). In the present study, we showed that the RGTA OTR4120 modulated angiogenesis in the chicken embryo chorioallantoic membrane assay, in a dose-dependent manner. We therefore investigated the effect of OTR4120 on one of the most specific angiogenesis-regulating heparin-binding growth factors, vascular endothelial growth factor 165 (VEGF165). OTR4120 showed high affinity binding to VEGF165 (Kd = 2.2 nm), as compared with heparin (Kd = 15 nm), and potentiated the affinity of VEGF165 for VEGF receptor-1 and -2 and for neuropilin-1. In vitro, OTR4120 potentiated VEGF165-induced proliferation and migration of human umbilical vein endothelial cells. In the in vivo Matrigel plug angiogenesis assay, OTR4120 in a concentration as low as 3 ng/ml caused a 6-fold increase in VEGF165-induced angiogenesis. Immunohistochemical staining showed a larger number of well differentiated VEGFR-2-expressing-cells in Matrigel sections of OTR4120-treated plug than in control sections. These findings indicate that OTR4120 enhances the VEGF165-induced angiogenesis and therefore may hold promise for treating disorders characterized by deficient angiogenesis.

Use of Enamel Matrix Protein Derivative Before Dental Reimplantation: A Histometric Analysis

The use of enamel matrix protein in the treatment of periodontal defects has shown a favorable action on the proliferation of periodontal ligament cells, as well as on collagen formation and mineralization. The goal was to evaluate, histologically and histometrically, periodontal tissue regeneration after dental reimplantation using enamel matrix protein derivative (Emdogain, Biora AB, Malmö, Sweden). Male rats (Albinus, Wistar), weighing between 180 and 200 g, were divided in 3 groups. Animals in group I (control) had the upper right incisors extracted, the root canal was sealed with calcium hydroxide, and teeth were reimplanted in their alveoli. Group II underwent the same procedure, but the remaining periodontal ligament was removed from the root surfaces by root planing before reimplantation. In group III,following removal of the periodontal ligament, Emdogain was applied to the root surfaces. Animals were sacrificed 7, 20, and 60 days after reimplantation, and the alveoli were fixed, processed, and stained with hematoxylin and eosin. Formation of periodontal ligament, resorption areas, and ankylosis were analyzed. The results showed that group I (control) was better than groups II and III, with statistically significant differences on days 7 and 20 after reimplantation for formation of periodontal ligament. It may be concluded that with the methodology used, Emdogain was unable to stimulate tissue repair in reimplanted teeth.

Disrupted G 1 to S phase clearance via cyclin signaling impairs liver tissue repair in thioacetamide-treated type 1 diabetic rats

Previously we reported that a nonlethal dose of thioacetamide (TA, 300 mg/kg) causes 90% mortality in type 1 diabetic (DB) rats because of irreversible acute liver injury owing to inhibited hepatic tissue repair, primarily due to blockage of G 0 to S phase progression of cell division cycle. On the other hand, DB rats receiving 30 mg TA/kg exhibited equal initial liver injury and delayed tissue repair compared to nondiabetic (NDB) rats receiving 300 mg TA/kg, resulting in a delay in recovery from liver injury and survival. The objective of the present study was to test the hypothesis that impaired cyclin-regulated progression of G 1 to S phase of the cell cycle may explain inhibited liver tissue repair, hepatic failure, and death, contrasted with delayed liver tissue repair but survival observed in the DB rats receiving 300 in contrast to 30 mg TA/kg. In the TA-treated NDB rats sustained MAPKs and cyclin expression resulted in higher phosphorylation of retinoblastoma (pRb), explaining prompt tissue repair and survival. In contrast, DB rats receiving the same dose of TA (300 mg/kg) exhibited suppressed MAPKs and cyclin expression that led to inhibition of pRb, inhibited tissue repair, and death. On the other hand, DB rats receiving 30 mg TA/kg exhibited delayed up regulation of MAPK signaling that delayed the expression of CD1 and pRb, explaining delayed stimulation of tissue repair observed in this group. In conclusion, the hepatotoxicant TA has a dose-dependent adverse effect on cyclin-regulated pRb signaling: the lower dose causes a recoverable delay, whereas the higher dose inhibits it with corresponding effect on the ultimate outcomes on hepatic tissue repair; this dose-dependent adverse effect is substantially shifted to the left of the dose response curve in diabetes.

Use of Prosthetic Mesh in Difficult Abdominal Wall Closure After Small Bowel Transplantation in Adults

Abdominal wall closure after intestinal transplantation in adult patients can be a difficult procedure. The main possibility offered by international experience is the use of myocutaneous flaps and abdominal wall transplantation. We report our experience in intestinal/multivisceral transplantation, including four difficult cases among 27 adult transplant recipients. Three patients underwent prosthetic mesh alone and one, a myocutaneous flap for abdominal closure after primary mesh positioning. We selected a mesh with a structure that allowed us to close the abdomen without creating adhesions and, at the same time, stimulating tissue repair. Two patients experienced local mesh infection, which has been kept under clinical control by antibiotics and daily medications till neoabdominal wall formation. The mesh was then removed. Another patient underwent mesh substitution for a suspicious fever. The last patient had mesh as a bridge for a subsequent myocutaneous flap from the thigh. All patients are in good health with well-functioning grafts and no need for parenteral nutrition. No enterocutaneous fistulae were detected.

Bone Morphogenetic Protein signaling in joint homeostasis and disease

Despite advances in therapies that target inflammation and tissue destruction in chronic arthritis, stimulation of tissue repair and restoration of joint function, the ultimate goal of treatment, is far from achieved. We introduce a new paradigm that may help to improve our understanding and management of chronic arthritis. The presence or absence of tissue responses distinguishes destructive arthritis, steady-state arthritis and remodeling arthritis. Increasing evidence suggests that reactivation of embryonic molecular pathways is an important mechanism to stimulate postnatal tissue repair. Bone Morphogenetic Proteins (BMPs) have critical roles in skeletal development and joint morphogenesis, but also in postnatal joint homeostasis and joint tissue remodeling. Therefore, modulation of BMP signaling may be an attractive therapeutic target in chronic arthritis to restore homeostasis and function of synovial joints.

Tissue Repair: An Important Determinant of Final Outcome of Toxicant-Induced Injury

Tissue repair is a dynamic compensatory cell proliferation and tissue regeneration response stimulated in order to overcome acute toxicity and recover organ/tissue structure and function. Extensive evidence in rodent models using structurally and mechanistically diverse hepatotoxicants such as acetaminophen (APAP), carbon tetrachloride (CCl4), chloroform (CHCl3), thioacetamide (TA), trichloroethylene (TCE), and allyl alcohol (AA) have demonstrated that tissue repair plays a critical role in determining the final outcome of toxicity, i.e., recovery from injury and survival or progression of injury leading to liver failure and death. Tissue repair is a complex process governed by intricate cellular signaling involving a number of chemokines, cytokines, growth factors, and nuclear receptors leading to promitogenic gene expression and cell division. Tissue repair also encompasses regeneration of hepatic extracellular matrix and angiogenesis, the processes necessary to completely restore the structure and function of the liver tissue lost to toxicant-induced initiation followed by progression of injury. New insights have emerged over the last quarter century indicating that tissue repair follows a dose response. Tissue repair increases with dose until a threshold dose, beyond which it is delayed and impaired due to inhibition of cellular signaling resulting in runaway secondary events causing tissue destruction, organ failure, and death. Prompt and adequately stimulated tissue repair response to toxic injury is critical for recovery from toxic injury. Tissue repair is modulated by a variety of factors including species, strain, age, nutrition, and disease condition causing marked changes in susceptibility and toxic outcome. This review focuses on the properties of tissue repair, different factors affecting tissue repair, and the mechanisms that govern tissue repair and progression of injury. It also highlights the significance of tissue repair as a target for drug development strategies and an important consideration in the assessment of risk from exposure to toxicants.

Transplanted human embryonic stem cells as biological ‘catalysts’ for tissue repair and regeneration

Human embryonic stem cells have tremendous potential in the newly emerging field of regenerative medicine. Recently, it was demonstrated that the rescue of lethal cardiac defects in Id knockout mutant mouse embryos was not due to the transplanted cells giving rise to functional new tissues within the defective embryonic heart. Instead, there is indirect evidence that the observed therapeutic effect was due to various secreted factors emanating from the transplanted cells. This therefore, introduces the exciting prospect of utilizing human embryonic stem cells as biological 'catalysts' to promote tissue repair and regeneration in transplantation therapy. However, the immunological barrier against allogenic transplantation, as well as the teratogenic potential of human embryonic stem cells poses major technical challenges. A possible strategy to overcome the immunological barrier may be to impose a temporary regimen of immunosuppressive drugs followed by their gradual withdrawal, once adequate tissue regeneration has been achieved. Other more novel alternatives include the use of microencapsulation to block interaction with the transplant recipient's immune system, and co-transplantation with bone marrow-derived mesenchymal stem cells, which have been demonstrated to possess immuno-suppressive properties. The teratogenic potential of human embryonic stem cells could possibly be alleviated by directing the differentiation of these cells to specific lineages prior to transplantation, or through mitotic inactivation (gamma irradiation or mitomycin C exposure). Co-transplantation with autologous adult stem cells may represent a novel strategy to further enhance the 'catalytic' effects of human embryonic stem cells. The various factors secreted by human embryonic stem cells could then have a concentrated localized effect on relatively large numbers of co-transplanted autologous adult stem cells, which may in turn lead to enhanced repair and regeneration of the damaged tissue or organ. Moreover, there is also a possibility that synergistic interactions between the co-transplanted human embryonic stem cells and autologous adult stem cells, may somehow produce signals for the recruitment and migration of additional endogenous adult stem cells within the recipient (i.e. peripheral blood circulation, bone marrow), which could further enhance organ/tissue regeneration. Hence, the potential use of human embryonic stem cells as biological 'catalysts' to stimulate tissue repair and regeneration, appears to hold tremendous promise in the field of regenerative medicine. This new therapeutic strategy needs to thoroughly investigated, in view of its potentially important clinical applications.