Normal Tissue Regeneration Research Articles

Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine

Mesenchymal stem cells (MSCs) are partially defined by their ability to differentiate into tissues including bone, cartilage and adipose in vitro, but it is their trophic, paracrine and immunomodulatory functions that may have the greatest therapeutic impact in vivo. Unlike pharmaceutical treatments that deliver a single agent at a specific dose, MSCs are site regulated and secrete bioactive factors and signals at variable concentrations in response to local microenvironmental cues. Significant progress has been made in understanding the biochemical and metabolic mechanisms and feedback associated with MSC response. The anti-inflammatory and immunomodulatory capacity of MSC may be paramount in the restoration of localized or systemic conditions for normal healing and tissue regeneration. Allogeneic MSC treatments, categorized as a drug by regulatory agencies, have been widely pursued, but new studies demonstrate the efficacy of autologous MSC therapies, even for individuals affected by a disease state. Safety and regulatory concerns surrounding allogeneic cell preparations make autologous and minimally manipulated cell therapies an attractive option for many regenerative, anti-inflammatory and autoimmune applications.

Prevention of Retrosternal Pericardial Adhesions After Cardiac Surgery With Mitomycin C

Retrosternal pericardial adhesions may cause significant injuries to the heart and great vessels in cases that require reoperation. Fibroblast proliferation is one of the mechanisms for adhesion formation. Inhibition of fibroblast proliferation is important in reduction of retrosternal adhesions. Mitomycin C (MMC) is able to reduce fibroblast proliferation. We aimed to determine the effect of MMC on prevention of retrosternal pericardial adhesions after primary cardiac operations. Thirty Sprague-Dawley female rats were used in the study. The rats were divided into two groups. First group was control (n=10) and second group was MMC study group (n=20). Xiphoid cartilage resection and retrosternal abrasion via subxiphoidal incision was performed. In the study group, MMC (1mg/kg) was topically applied to the retrosternal space. After 15 days, rats were taken into reoperation and adhesion was graded. Tissue and blood samples were taken before termination procedure. Standard staining procedures and fibroblast growth factor receptor 3 antibody staining, were applied immunohistochemically to tissue samples. The average adhesion scores of the control (n=10) and study (n=20) (MMC; 1mg/kg) groups were 2.50 ± 1.27 and 0.70 ± 0.86, respectively. The adhesion score of the study group was lower than the control group (p<0.05). Immunohistochemical samples revealed that tissue fibroblast intensity was significantly higher in the control group than the study group (p<0.05). There was no statistical significance between two groups in case of hydroxyproline levels (p>0.05). MMC was found to be effective in the prevention of retrosternal pericardial adhesions without any delay in normal tissue regeneration.

Mouse Adipose Tissue-Derived Adult Stem Cells Expressed Osteogenic Specific Transcripts of Osteocalcin and Parathyroid Hormone Receptor During Osteogenesis

IntroductionAdult mesenchymal stem cells (MSCs) have potential to differentiate into various lineages, replacing cells during normal turnover and tissue regeneration to replace damaged or lost adult tissues during osteoporosis and arthritis, or traumatic injuries. We investigated the osteogenic signature in mouse adipose tissue (AD)- and bone marrow (BM)-derived MSCs. Materials and MethodsMSCs from adipose tissue and bone marrow were compared for osteogenic endogenous mRNA markers by reverse-transcription polymerase chain reaction (RT-PCR). Cellular proliferation and immunophenotype analyzed by flow cytometry revealed that mouse AD-MSCs and BM-MSCs shared similar characteristics. ResultIsolated AD-MSC and BM-MSC showed high proliferation rates and fibroblast morphology. Flow cytometry revealed positive markers for mesenchyme, but negative for primitive hematopoietic and endothelial cells. At day 21, Alizarin red S and Von-kossa staining of differentiated cells showed high calcium deposits compared with undifferentiated cells. After 21 days of osteogenic differentiation, AD-MSCs expressed osteocalcin and parathyroid hormone (PTH) compared with undifferentiated cells. Osteogenic-specific transcript of osteocalcin (OC), bone gamma carboxyglutamate protein, and PTH receptor (PTHr) were detected only in differentiated not undifferentiated cells. Undifferentiated BM-MSCs, expressed all markers at low intensity, which amplified during differentiation. ConclusionOur findings suggest that the OC and PTHr can be used as differentiation markers for osteogenesis of mouse AD-MSC.

Epoxyeicosanoids promote organ and tissue regeneration

Epoxyeicosatrienoic acids (EETs), lipid mediators produced by cytochrome P450 epoxygenases, regulate inflammation, angiogenesis, and vascular tone. Despite pleiotropic effects on cells, the role of these epoxyeicosanoids in normal organ and tissue regeneration remains unknown. EETs are produced predominantly in the endothelium. Normal organ and tissue regeneration require an active paracrine role of the microvascular endothelium, which in turn depends on angiogenic growth factors. Thus, we hypothesize that endothelial cells stimulate organ and tissue regeneration via production of bioactive EETs. To determine whether endothelial-derived EETs affect physiologic tissue growth in vivo, we used genetic and pharmacological tools to manipulate endogenous EET levels. We show that endothelial-derived EETs play a critical role in accelerating tissue growth in vivo, including liver regeneration, kidney compensatory growth, lung compensatory growth, wound healing, corneal neovascularization, and retinal vascularization. Administration of synthetic EETs recapitulated these results, whereas lowering EET levels, either genetically or pharmacologically, delayed tissue regeneration, demonstrating that pharmacological modulation of EETs can affect normal organ and tissue growth. We also show that soluble epoxide hydrolase inhibitors, which elevate endogenous EET levels, promote liver and lung regeneration. Thus, our observations indicate a central role for EETs in organ and tissue regeneration and their contribution to tissue homeostasis.

Transforming growth factor-β1 selectively inhibits hepatocyte growth factor expression via a micro-RNA-199–dependent posttranscriptional mechanism

Hepatocyte growth factor (HGF) is a multipotent endogenous repair factor secreted primarily by mesenchymal cells with effects on cells expressing its receptor, Met. HGF promotes normal tissue regeneration and inhibits fibrotic remodeling in part by promoting proliferation and migration of endothelial and epithelial cells and protecting these cells from apoptosis. HGF also inhibits myofibroblast proliferation. The profibrotic cytokine transforming growth factor beta 1 (TGF-β1) suppresses HGF expression but not the expression of NK2, an HGF splice variant that antagonizes HGF-induced proliferation. We investigated the mechanism for differential regulation of HGF and NK2 by TGF-β1. TGF-β1 down-regulated HGF in primary human adult pulmonary fibroblasts (HLFb) and increased the expression of miR-199a-3p, a microRNA (miRNA) associated with fibrotic remodeling. HGF and NK2 contain completely different 3' untranslated regions (UTRs), and we determined that miR-199a-3p targeted HGF mRNA for suppression but not NK2. A pre-miR-199 mimic inhibited the expression of a luciferase reporter harboring the HGF 3' UTR but not a pmirGLO reporter containing the NK2 3' UTR. In contrast, an anti-miRNA inhibitor specific for miR-199a-3p prevented TGF-β1-induced reduction of both HGF mRNA and HGF protein secretion. Taken together, these findings demonstrate that HGF is distinctly regulated at the posttranscriptional level from its antagonist NK2.

Gelatin crosslinked with dehydroascorbic acid as a novel scaffold for tissue regeneration with simultaneous antitumor activity

A porous scaffold was developed to support normal tissue regeneration in the presence of residual tumor disease. It was prepared by gelatin crosslinked with dehydroascorbic acid (DHA). A physicochemical characterization of the scaffold was carried out. SEM and mercury porosimetry revealed a high porosity and interconnection of pores in the scaffold. Enzymatic degradation provided 56% weight loss in ten days. The scaffold was also evaluated in vitro for its ability to support the growth of normal cells while hindering tumor cell development. For this purpose, primary human fibroblasts and osteosarcoma tumor cells (MG-63) were seeded on the scaffold. Fibroblasts attached the scaffold and proliferated, while the tumor cells, after an initial attachment and growth, failed to proliferate and progressively underwent cell death. This was attributed to the progressive release of DHA during the scaffold degradation and its cytotoxic activity towards tumor cells.

SP-0306: Improving post-irradiation normal tissue regeneration using paracrine stimulation

SP-0306: Improving post-irradiation normal tissue regeneration using paracrine stimulation

Cellular Response to a Novel Fetal Acellular Collagen Matrix: Implications for Tissue Regeneration

Introduction. PriMatrix (TEI Biosciences Inc., Boston, MA, USA) is a novel acellular collagen matrix derived from fetal bovine dermis that is designed for use in partial- and full-thickness wounds. This study analyzes the cellular response to PriMatrix in vivo, as well as the ability of this matrix to facilitate normal tissue regeneration. Methods. Five by five mm squares of rehydrated PriMatrix were implanted in a subcutaneous fashion on the dorsum of wild-type mice. Implant site tissue was harvested for histology, immunohistochemistry (IHC), and flow cytometric analyses at multiple time points until day 28. Results. PriMatrix implants were found to go through a biological progression initiated by a transient infiltrate of inflammatory cells, followed by mesenchymal cell recruitment and vascular development. IHC analysis revealed that the majority of the implanted fetal dermal collagen fibers persisted through day 28 but underwent remodeling and cellular repopulation to form tissue with a density and morphology consistent with healthy dermis. Conclusions. PriMatrix implants undergo progressive in vivo remodeling, facilitating the regeneration of histologically normal tissue through a mild inflammatory and progenitor cell response. Regeneration of normal tissue is especially important in a wound environment, and these findings warrant further investigation of PriMatrix in this setting.

Normal tissue protection for improving radiotherapy: Where are the Gaps?

Any tumor could be controlled by radiation therapy if sufficient dose were delivered to all tumor cells. Although technological advances in physical treatment delivery have been developed to allow more radiation dose conformity, normal tissues are invariably included in any radiation field within the tumor volume and also as part of the exit and entrance doses relevant for particle therapy. Mechanisms of normal tissue injury and related biomarkers are now being investigated, facilitating the discovery and development of a next generation of radiation protectors and mitigators. Bringing recent research advances stimulated by development of radiation countermeasures for mass casualties, to clinical cancer care requires understanding the impact of protectors and mitigators on tumor response. These may include treatments that modify cellular damage and death processes, inflammation, alteration of normal flora, wound healing, tissue regeneration and others, specifically to counter cancer site-specific adverse effects to improve outcome of radiation therapy. Such advances in knowledge of tissue and organ biology, mechanisms of injury, development of predictive biomarkers and mechanisms of radioprotection have re-energized the field of normal tissue protection and mitigation. Since various factors, including organ sensitivity to radiation, cellular turnover rate, and differences in mechanisms of injury manifestation and damage response vary among tissues, successful development of radioprotectors/mitigators/treatments may require multiple approaches to address cancer site specific needs. In this review, we discuss examples of important adverse effects of radiotherapy (acute and intermediate to late occurring, when it is delivered either alone or in conjunction with chemotherapy, and important limitations in the current approaches of using radioprotectors and/or mitigators for improving radiation therapy. Also, we are providing general concepts for drug development for improving radiation therapy.

Fluorodeoxyglucose Positron Emission Tomography Response and Normal Tissue Regeneration After Stereotactic Body Radiotherapy to Liver Metastases

To characterize changes in standardized uptake value (SUV) in positron emission tomography (PET) scans and determine the pace of normal tissue regeneration after stereotactic body radiation therapy (SBRT) for solid tumor liver metastases. We reviewed records of patients with liver metastases treated with SBRT to ≥40 Gy in 3-5 fractions. Evaluable patients had pretreatment PET and ≥1 post-treatment PET. Each PET/CT scan was fused to the planning computed tomography (CT) scan. The maximum SUV (SUV(max)) for each lesion and the total liver volume were measured on each PET/CT scan. Maximum SUV levels before and after SBRT were recorded. Twenty-seven patients with 35 treated liver lesions were studied. The median follow-up was 15.7 months (range, 1.5-38.4 mo), with 5 PET scans per patient (range, 2-14). Exponential decay curve fitting (r=0.97) showed that SUV(max) declined to a plateau of 3.1 for controlled lesions at 5 months after SBRT. The estimated SUV(max) decay half-time was 2.0 months. The SUV(max) in controlled lesions fluctuated up to 4.2 during follow-up and later declined; this level is close to 2 standard deviations above the mean normal liver SUV(max) (4.01). A failure cutoff of SUV(max) ≥6 is twice the calculated plateau SUV(max) of controlled lesions. Parenchymal liver volume decreased by 20% at 3-6 months and regenerated to a new baseline level approximately 10% below the pretreatment level at 12 months. Maximum SUV decreases over the first months after SBRT to plateau at 3.1, similar to the median SUV(max) of normal livers. Transient moderate increases in SUV(max) may be observed after SBRT. We propose a cutoff SUV(max) ≥6, twice the baseline normal liver SUV(max), to score local failure by PET criteria. Post-SBRT values between 4 and 6 would be suspicious for local tumor persistence or recurrence. The volume of normal liver reached nadir 3-6 months after SBRT and regenerated within the next 6 months.

A new clinical approach: Use of blood-derived stem cells (BDSCs) for superficial digital flexor tendon injuries in horses

AimsIn this study, we present an innovative therapy using stem cells that were obtained from the peripheral blood of racehorses affected by uninduced superficial digital flexor tendon (SDFT) injuries. Main methodsBlood-derived stem cells (BDSCs) were generated from the blood samples of three horses in the presence of macrophage colony-stimulating factor (M-CSF). The racehorses received a single autologous BDSC treatment, which resulted in the successful repair of the tendons injuries. Key findingsThe results demonstrated that the BDSCs injection into the damaged tendon stimulated the regeneration of normal tissue. Furthermore, a relationship may exist between the speed and the quality of new tissue formation and the welfare and management of the treated animals. SignificanceThis study demonstrates that stem cell technology offers new tools for tissue repair that in many cases is considered incurable, and provides additional evidence that BDScs injections increase the speed and quality of the regeneration process in different animal tissues.

The Effect of Platelet-rich Plasma on Wounds of OLETF Rats Using Expression of Matrix Metalloproteinase-2 and -9 mRNA

BackgroundComplicated diabetic patients show impaired, delayed wound healing caused by multiple factors. A study on wound healing showed that platelet-rich plasma (PRP) was effective in normal tissue regeneration. Nonetheless, there is no evidence that when plateletrich plasma is applied to diabetic wounds, it normalizes the diabetic wound healing process. In this study, we have analyzed matrix metalloproteinase (MMP)-2, MMP-9 expression to investigate the effect of PRP on diabetic wounds.MethodsTwenty-four-week-old male Otsuka Long-Evans Tokushima Fatty rats were provided by the Tokushima Research Institute. At 50 weeks, wounds were arranged in two sites on the lateral paraspinal areas. Each wound was treated with PRP gel and physiologic saline gauze. To determine the expression of MMP-2, MMP-9, which was chosen as a marker of wound healing, reverse transcription polymerase chain reaction (RT-PCR) was performed and local distribution and expression of MMP-2, MMP-9 was also observed throughout the immunohistochemical staining.ResultsRT-PCR and the immunohistochemical study showed that the levels of MMP-2, MMP-9 mRNA expression in PRP applied tissues were higher than MMP-2, MMP-9 mRNA expression in saline-applied tissues. MMP-9 mRNA expression in wounds of diabetic rats decreased after healing began to occur. But no statistical differences were detected on the basis of body weight or fasting blood glucose levels.ConclusionsThis study could indicate the extracellular matrix-regulating effect observed with PRP. Our results of the acceleration of wound healing events by PRP under hyperglycemic conditions might be a useful clue for future clinical treatment for diabetic wounds.

Sox2 + Adult Stem and Progenitor Cells Are Important for Tissue Regeneration and Survival of Mice

The transcription factor Sox2 maintains the pluripotency of early embryonic cells and regulates the formation of several epithelia during fetal development. Whether Sox2 continues to play a role in adult tissues remains largely unknown. We show here that Sox2 marks adult cells in several epithelial tissues where its expression has not previously been characterized, including the stomach, cervix, anus, testes, lens, and multiple glands. Genetic lineage tracing and transplantation experiments demonstrate that Sox2-expressing cells continuously give rise to mature cell types within these tissues, documenting their self-renewal and differentiation potentials. Consistent with these findings, ablation of Sox2(+) cells in mice results in a disruption of epithelial tissue homeostasis and lethality. Developmental fate mapping reveals that Sox2(+) adult stem cells originate from fetal Sox2(+) tissue progenitors. Thus, our results identify Sox2 expression in numerous adult endodermal and ectodermal stem cell compartments, which are critical for normal tissue regeneration and survival.

SILAC zebrafish for quantitative analysis of protein turnover and tissue regeneration

Defective tissue regeneration is thought to contribute to several human diseases, including neurodegenerative disorders, heart failure and various lung diseases. Boosting the regenerative capacity has been suggested a possible therapeutic approach. Methods to metabolically label newly synthesized proteins in vivo with stable isotopic forms of amino acids holds promise for the study of protein turnover and tissue regeneration that are fundamental to the sustained life of all organisms. Here, we used the "stable isotope labeling with amino acids in cell culture" (SILAC) approach to explore normal protein turnover and tissue regeneration in adult zebrafish. The ratio of labeled and unlabeled proteins/peptides in specific organs of zebrafish fed a SILAC diet containing (13)C(6)-labeled lysine was determined by liquid chromatography and tandem mass spectrometry. Labeling was highest in tissues with high regenerative capacity, including intestine, liver, and fin, whereas brain and heart displayed the lowest labeling. Proteins with high degree of labeling were mainly involved in catalytic or transport activity pathways. The technique also verified increased protein synthesis during regeneration of the caudal fin following amputation. This newly developed SILAC zebrafish model constitutes a novel tool to analyze tissue regeneration in an animal model amenable to genetic and pharmacologic manipulation.

Wnt signalling and its role in stem cell‐driven intestinal regeneration and hyperplasia

Adult stem cells are crucial for normal tissue homeostasis and regeneration upon damage. Deregulated stem cell proliferation and/or differentiation have been linked to the formation and progression of tumours. Due to its high regenerative potential, the adult intestinal epithelium is an excellent system to study the mechanisms that underpin regeneration and transformation. Since the discovery of stem cell markers in the mammalian intestine - such as Lgr5 - and the presence of Drosophila intestinal stem cells there have been field-changing discoveries that have revolutionized our understanding of intestinal homeostasis, stem cells and transformation. We will thus present a brief overview of these advances with an emphasis on the role of canonical Wnt signalling and the lessons learned from genetic tractable model systems.

Quantitative Interpretation of a Genetic Model of Carcinogenesis Using Computer Simulations

The genetic model of tumorigenesis by Vogelstein et al. (V theory) and the molecular definition of cancer hallmarks by Hanahan and Weinberg (W theory) represent two of the most comprehensive and systemic understandings of cancer. Here, we develop a mathematical model that quantitatively interprets these seminal cancer theories, starting from a set of equations describing the short life cycle of an individual cell in uterine epithelium during tissue regeneration. The process of malignant transformation of an individual cell is followed and the tissue (or tumor) is described as a composite of individual cells in order to quantitatively account for intra-tumor heterogeneity. Our model describes normal tissue regeneration, malignant transformation, cancer incidence including dormant/transient tumors, and tumor evolution. Further, a novel mechanism for the initiation of metastasis resulting from substantial cell death is proposed. Finally, model simulations suggest two different mechanisms of metastatic inefficiency for aggressive and less aggressive cancer cells. Our work suggests that cellular de-differentiation is one major oncogenic pathway, a hypothesis based on a numerical description of a cell's differentiation status that can effectively and mathematically interpret some major concepts in V/W theories such as progressive transformation of normal cells, tumor evolution, and cancer hallmarks. Our model is a mathematical interpretation of cancer phenotypes that complements the well developed V/W theories based upon description of causal biological and molecular events. It is possible that further developments incorporating patient- and tissue-specific variables may build an even more comprehensive model to explain clinical observations and provide some novel insights for understanding cancer.

Chimeric fibronectin matrix mimetic as a functional growth- and migration-promoting adhesive substrate

Therapeutic protein engineering combines genetic, biochemical, and functional information to improve existing proteins or invent new protein technologies. Using these principles, we developed an approach to deliver extracellular matrix (ECM) fibronectin-specific signals to cells. Fibronectin matrix assembly is a cell-dependent process that converts the inactive, soluble form of fibronectin into biologically-active ECM fibrils. ECM fibronectin stimulates cell functions required for normal tissue regeneration, including cell growth, spreading, migration, and collagen reorganization. We have developed recombinant fibronectin fragments that mimic the effects of ECM fibronectin on cell function by coupling the cryptic heparin-binding fragment of fibronectin’s first type III repeat (FNIII1H) to the integrin-binding domain (FNIII8–10). GST/III1H,8–10 supports cell adhesion and spreading and stimulates cell proliferation to a greater extent than plasma fibronectin. Deletion and site-specific mutant constructs were generated to identify the active regions in GST/III1H,8–10 and reduce construct size. A chimeric construct in which the integrin-binding, RGDS loop was inserted into the analogous site in FNIII8 (GST/III1H,8RGD), supported cell adhesion and migration, and enhanced cell proliferation and collagen gel contraction. GST/III1H,8RGD was expressed in bacteria and purified from soluble lysate fractions by affinity chromatography. Fibronectin matrix assembly is normally up-regulated in response to tissue injury. Decreased levels of ECM fibronectin are associated with non-healing wounds. Engineering fibronectin matrix mimetics that bypass the need for cell-dependent fibronectin matrix assembly in chronic wounds is a novel approach to stimulating cellular activities critical for tissue repair.

Tumor necrosis factor alpha promotes the expression of immunosuppressive proteins and enhances the cell growth in a human bone marrow-derived stem cell culture

Mesenchymal stem cells (MSCs) are widely used in experimental treatments for various conditions that involve normal tissue regeneration via inflammatory repair. It is known that MSCs can secrete multiple soluble factors and suppress inflammation. Even though the effect of MSCs on inflammation has been extensively studied, the effect of inflammation on MSCs is poorly understood. One of the major cytokines released at the site of inflammation is tumor necrosis factor alpha (TNF-α) which is known to induce MSC invasion and proliferation. Therefore, we wanted to test the effects of TNF-α exposure on MSCs derived from human bone marrow. We found, as expected, that cell proliferation was significantly enhanced during TNF-α exposure. However, according to the cell surface marker analysis, the intensity of several antigens in the minimum criteria panel for MSCs proposed by International Society of Cellular Therapy (ISCT) was decreased dramatically, and in certain cases, the criteria for MSCs were not fulfilled. In addition, TNF-α exposure resulted in a significant but transient increase in human leukocyte antigen and CD54 expression. Additional proteomic analysis by two-dimensional difference gel electrophoresis and mass spectrometry revealed three proteins whose expression levels decreased and 8 proteins whose expression levels increased significantly during TNF-α exposure. The majority of these proteins could be linked to immunosuppressive and signalling pathways. These results strongly support reactive and immunosuppressive activation of MSCs during TNF-α exposure, which might influence MSC differentiation stage and capacity.

Differential Regulation of Growth-Promoting Signalling Pathways by E-Cadherin

BackgroundDespite the well-documented association between loss of E-cadherin and carcinogenesis, as well as the link between restoration of its expression and suppression of proliferation in carcinoma cells, the ability of E-cadherin to modulate growth-promoting cell signalling in normal epithelial cells is less well understood and frequently contradictory. The potential for E-cadherin to co-ordinate different proliferation-associated signalling pathways has yet to be fully explored.Methodology/Principal FindingsUsing a normal human urothelial (NHU) cell culture system and following a calcium-switch approach, we demonstrate that the stability of NHU cell-cell contacts differentially regulates the Epidermal Growth Factor Receptor (EGFR)/Extracellular Signal-Regulated Kinase (ERK) and Phosphatidylinositol 3-Kinase (PI3-K)/AKT pathways. We show that stable cell contacts down-modulate the EGFR/ERK pathway, whilst inducing PI3-K/AKT activity, which transiently enhances cell growth at low density. Functional inactivation of E-cadherin interferes with the capacity of NHU cells to form stable calcium-mediated contacts, attenuates E-cadherin-mediated PI3-K/AKT induction and enhances NHU cell proliferation by allowing de-repression of the EGFR/ERK pathway and constitutive activation of β-catenin-TCF signalling.Conclusions/SignificanceOur findings provide evidence that E-cadherin can differentially and concurrently regulate specific growth-related signalling pathways in a context-specific fashion, with direct, functional consequences for cell proliferation and population growth. Our observations not only reveal a novel, complex role for E-cadherin in normal epithelial cell homeostasis and tissue regeneration, but also provide the basis for a more complete understanding of the consequences of E-cadherin loss on malignant transformation.

Wound Healing Versus Regeneration: Role of the Tissue Environment in Regenerative Medicine.

One of the major challenges in the field of regenerative medicine is how to optimize tissue regeneration in the body by therapeutically manipulating its natural ability to form scar at the time of injury or disease. It is often the balance between tissue regeneration, a process that is activated at the onset of disease, and scar formation, which develops as a result of the disease process that determines the ability of the tissue or organ to be functional. Using biomaterials as scaffolds often can provide a "bridge" for normal tissue edges to regenerate over small distances, usually up to 1 cm. Larger tissue defect gaps typically require both scaffolds and cells for normal tissue regeneration to occur without scar formation. Various strategies can help to modulate the scar response and can potentially enhance tissue regeneration. Understanding the mechanistic basis of such multivariate interactions as the scar microenvironment, the immune system, extracellular matrix, and inflammatory cytokines may enable the design of tissue engineering and wound healing strategies that directly modulate the healing response in a manner favorable to regeneration.