Current Stem Cell Research & Therapy - Volume 5, Issue 2, 2010

Adipose-derived stem cells (ASCs) have been studied widely since the publication in 2001 of the first report on this type of stem cells. Since then, knowledge on their characterization, immunological characteristics, and potential of multilineage differentiation has been accumulating dramatically. Many international medical conferences have selected ASCs as a main topic. In addition, the International Federation of Adipose Therapeutics and Science (IFATS) has been extremely active in promoting the study and discussion of ASCs internationally. However, there are no publications on ASCs that used a structured approach. Thus, we have dedicated a special issue of the journal “Current Stem Cell Research and Therapy” to “Adipose-Derived Stem Cells”. This special issue targeted the basic biology and potential role of ASCs for the treatment/regeneration of cells, tissues, and organs throughout the body, e.g., fat, bone, cartilage, skeletal muscle, skin, vessels, heart, nerve, tendons, periodontal tissue, vocal fold, liver, pancreas, and cornea. Induced-pluripotent stem cells (iPS cells) and embryonic stem cells (ESCs) have received much attention recently; however, I believe that ASCs retain great advantages, such as their accessibility, manageability, and safety. Several companies have targeted their products on ASCs. In addition, clinical applications of ASCs are underway worldwide and their effects are now being reported. I am happy that internationally renowned clinical/basic scientists have joined this book and reviewed the most recent advances in adipose-tissue biology, current strategy of tissue regeneration, and future perspectives. I hope that this special issue will bring together basic scientists and clinicians in different countries and contribute to the development of stem-cell research. Finally, I would like to thank Ms Shabana Seemee at Bentham Science Publishers for her tremendous help, whihc was essential for the completion of this special issue.

Adipose tissue is an attractive source of multipotent adult stem cells due to its wide-spread availability, accessibility, and ease of harvest. Adipose-derived stem cells (ASCs), the adherent stromal cell population present within adipose tissue, are easily expanded in culture, able to differentiate along multiple cell-lineage pathways, and have been shown to provide therapeutic benefit in models of injury and disease through immunomodulation, structural integation, and/or trophic support. Recent developments in the characterization of ASCs, specifically their isolation, gene and protein expression, differentiation, and expansion, are reviewed in this article.

Stem cells have been long looked at as possible therapeutic vehicles for different health related problems. Among the different existing stem cell populations, Adipose derived Stem Cells (ASCs) have been gathering attention in the last 10 years. When compared to other stem cells populations and sources, ASCs can be easily isolated while providing higher yields upon the processing of adipose tissue. Similar to other stem cell populations, it was initially thought that the main potential of ASCs for regenerative medicine approaches was intimately related to their differentiation capability. Although this is true, there has been an increasing body of literature describing the trophic effects of ASCs on the protection, survival and differentiation of a variety of endogenous cells/tissues. Moreover, they have also shown to possess an immunomodulatory character. This effect is closely related to the ASCs' secretome and the soluble factors found within it. Molecules such as hepatocyte growth factor (HGF), granulocyte and macrophage colony stimulating factors, interleukins (ILs) 6, 7, 8 and 11, tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF), brain derived neurotrophic factor (BDNF), nerve growth factor (NGF), adipokines and others have been identified within the ASCs' secretome. Due to its importance regarding future applications for the field of regenerative medicine, we aim, in the present review, to make a comprehensive analysis of the literature relating to the ASCs' secretome and its relevance to the immune and central nervous system, vascularization and cardiac regeneration. The concluding section will highlight some of the major challenges that remain before ASCs can be used for future clinical applications.

Allergic rhinitis and asthma are inflammatory airway allergic diseases caused by Th2-driven immune response. Several studies have shown that multipotent adipose-derived stem cells (ASCs) can exert profound immunosuppressive effects via modulation of both cellular and innate immune pathway, especially immunosuppressive effect on T cell activities. ASCs' ability to be readily isolated from a number of adipose tissues and expanded ex vivo makes them attractive candidate for use in clinical therapy in the context of allogeneic transplantation, in particular to modulate graft-versus-host disease and graft rejection. The authors have investigated whether ASCs can inhibit Th2-dependent airway allergic disease in the mouse model. In this article we review recent experimental data and discuss about the mechanisms by which ASCs inhibit allergic airway inflammation via immunomodulation from a Th2 to a Th1-biased response in the mouse model.

The repair of soft tissue defects, particularly after trauma and oncologic surgery, represents a major clinical challenge. While current reconstructive procedures can move soft tissue from other areas of the body, there remains an unmet need for new modalities that are less invasive and more precise. Adipose tissue is the key component necessary for soft tissue reconstruction. This review will discuss the discovery and potential of adult stem therapies in the regeneration of adipose tissue. Adipose-derived stem cells (ASCs), are being examined as cell delivery systems for soft tissue reconstruction. In addition to a further understanding of the biology of ASCs, appropriate biomaterials (e.g., cell delivery vehicles), rapid expansion of stem cells using bioreactors, and suitable animal models for adipose tissue engineering are needed for successful stem cell therapies, and will be discussed in this review. Clinical studies with ASCs are being conducted in Europe and Asia and will be described.

In the face of mounting clinical demand, and armed with reconstructive techniques that are technically challenging and frequently result in suboptimal patient outcomes, increasing focus is being placed on tissue engineering and regenerative medicine as a potential source of novel skeletal reconstructive approaches. Specifically, evidence is accumulating that highlights the promise of osteoprogenitor cell-based reconstructive strategies to meet the needs of an expanding patient population. Historically, the study of cell and molecular biology guiding physiologic and pathologic skeletal development, as well as endogenous bone regeneration following injury, has provided a wealth of information that lends insight toward potential parallel processes that may regulate the osteogenic differentiation of progenitor cells. Multiple progenitor cell populations are now known to possess a capacity to undergo robust osteogenic differentiation in the presence of appropriate environmental cues (hESC, BMSC, ASC, etc.) Recent investigations have put forth multiple advantages of ASC relative to BMSC. Of note, ASC exist in relative abundance, lack the need for in vitro expansion prior to utilization, and can be harvested with relative ease and reduced donor morbidity. Collectively, these factors, paired with promising in vitro and in vivo observations that speak toward the substantial osteogenic potential of ASC, have spurred enthusiasm to pursue the application of ASC in the maturation of skeletal tissue engineering applications. Yet, elucidating what structural and functional properties of scaffolds designed for ASC-mediated skeletal tissue engineering applications (porosity, pore size, composition, mechanical stability, degradation kinetics, etc.), as well as evolving our understanding and capacity to deliver spatiotemporally specific pro-osteogenic targeted molecular manipulation to progenitor cells, remain important hurdles to clear. The scope of this review encompasses the current state of ongoing investigations along these fronts, as well as what future direction will be critical to the transition of cell-based skeletal tissue engineering strategies to the bedside.

The first tissue engineering product, autologous chondrocytes implantation or transplantation (ACI or ACT), has been available for over a decade. Recently, adult tissue-derived stem cells have received great interest for their ability to promote tissue regeneration. To date, adipose-derived stem cells (ASCs) have been evaluated for new surgical procedures to reconstruct damaged and defective tissue, because they are easiest to harvest due to the large number of stem cells compared to other stem cell sources. However, there are issues in using ASCs for cartilage repair. Thus, we need more information regarding optimal culture conditions and methods to promote chondrogenic lineages of stem cells. The necessary information includes necessary differentiation factors, cell scaffolds, and cell culture conditions. We reviewed the methodology for manufacturing cell constructs using ASCs for clinical applications.

Stem cell based therapies for the repair and regeneration of various tissues and organs offer a paradigm shift that may provide alternative therapeutic solutions for a number of diseases. This review focuses on skeletal muscle regeneration and repair by adipose-derived stem cells (ASCs) with particular attention to their potential use as a therapy for disorders such as degenerative muscle diseases or skeletal muscle injuries. ASCs can differentiate into skeletal muscle cells in vitro either in co-culture with skeletal myoblasts, or when cultured in medium supplemented with horse serum and/or under reduced serum conditions. In particular, spontaneous fusion of ASCs and subsequent myotube-like formation was observed in early culture passages at high cell density. ASCs have also shown a capacity for myogenic differentiation in vivo. In a murine muscular dystrophy model, ASCs were able to restore muscle function following direct injection into the affected muscle as well as following intravenous systemic administration. Of great importance is the finding that allogeneic ASCs injected into the damaged muscle were not rejected, even without immunosuppressive therapy. Because human adipose tissue is ubiquitous and easily obtainable in large quantities under local anesthesia with little patient discomfort, it presents an appealing source of stem cells for mesenchymal tissue regeneration and engineering.

With the discovery of adipose stem cells (ASCs), 40 years after the identification of bone marrow stem cells, a new era of active stem cell therapy has opened. The abundance of stem cells harvested from adipose tissue enables us to instantly apply primary cells without culture expansion. ASCs are already clinically applied in many other purposes such as cell-enriched lipotransfer, wound healing, skin rejuvenation, scar remodeling and skin tissue engineering. Although cellular mechanism of ASCs is not completely understood, recent researches have disclosed some of their unique functions as mesenchymal stem cells. There have been increasing numbers of scientific reports on the therapeutic effect of ASCs on skin repair, scar remodeling and rejuvenation. Wound healing and scar remodeling are complex, multi-cellular processes that involve coordinated efforts of many cell types and various cytokines. Recent reports showed ASCs as a powerful source of skin regeneration because of their capability to provide not only cellular elements, but also numerous cytokines. Currently, other attractive functions of ASCs in the recovery of extrinsic aging and radiation damage are under active investigation. It seems that autologous ASCs have great promise for applications in repair of skin, rejuvenation of aging skin and aging-related skin lesions. This review will focus on the specific roles of ASCs in skin tissue, especially related with wound healing, radiation injury, scar remodeling, skin rejuvenation and skin engineering.

Adipose tissue is the final tissue to develop and is strongly involved in energy homeostasis. It can represent up to 50% of body weight in obesity. Beside its metabolic role, endocrine functions appeared to play a key role in interconnecting adipose tissue with other tissues of the organism and in numerous physiological functions. The presence of adipocyte progenitors has long been demonstrated throughout life in the stromal fraction of adipose tissue. Now, it appears that these cells are multipotent and share numerous features with mesenchymal stem cells (MSC) derived from bone marrow. They also display some specificities and a strong pro-angiogenic potential. Altogether, these data emphasize the need to reconsider the potential of adipose tissue. Moreover, since fat pads are easy to sample, numerous and promising perspectives are now opening up in regenerative medicine, particularly in ischemic situations.

Stem cell biology has increasingly gained scientific and public interest in recent years. In particular, the use of stem cells for treatment of heart disease has been strongly pursued within the scientific and medical communities. Significant effort has gone into the use of adult tissue-derived stem cells for cardiac repair including bone marrow, blood, and cardiac-derived cell populations. Significant interest in this area has been balanced by the difficulties of understanding stem cells, cardiac injury, and the amalgamation of these areas of investigation in translational medicine. Recent studies have emerged on adipose-derived stem cells which show the potential for cardiac lineage development in vitro and may have application in cell-mediated in vivo therapy for the diseased heart. This review provides a summary of current findings within the field of adipose-derived stem cell biology regarding their cardiac differentiation potential.

Neural tissue has historically been regarded as having poor regenerative capacity but recent advances in the growing fields of tissue engineering and regenerative medicine have opened new hopes for the treatment of nerve injuries and neurodegenerative disorders. Adipose tissue has been shown to contain a large quantity of adult stem cells (ASC). These cells can be easily harvested with low associated morbidity and because of their potential to differentiate into multiple cell types, their use has been suggested for a wide variety of therapeutic applications. In this review we examine the evidence indicating that ASC can stimulate nerve regeneration by both undergoing neural differentiation and through the release of a range of growth factors. We also discuss some of the issues that need to be addressed before ASC can be developed as an effective cellular therapy for the treatment of neural tissue disorders.

Tendon, the crucial element of the musculoskeletal system, when damaged, never restores the biological and biomechanical properties completely. Recently, tissue engineering and regenerative medicine have enabled the differentiation of postnatal somatic stem cells or mesenchymal stem cells (MSCs) to different cell lineages and tissues including tendon. In addition, the MSCs, mainly bone marrow derived stem cells (BSCs) were proven to enhance tendon healing. Adipose derived stem cells (ASCs) were shown to be as effective as the other MSCs by their multipotency and proliferative efficiency. However, neither the differentiation of ASCs to tenocytes nor the tendon regeneration using ASCs have been described in literature. Recently, we have studied the effect of ASCs on primary tendon repair in in-vivo model. In this paper, we sought to discuss tendon tissue engineering by focusing on culture of tenocytes, biomaterials, scaffolds, mechanical loading, fibroblasts and mesenchymal stem cells and mainly on adipose derived stem cells. Tendon regeneration using ASCs might be one of the clinical remedies in near future. In addition, the enhancing effect of ASCs on tendon repair and tendon defects might enable better clinical outcomes in musculoskeletal system reconstruction. Advances in biomaterial technology will improve the methodology in tendon regeneration however, up to date, ASCs present an ideal cell source for experimental and clinical research on tendon engineering.

Periodontal disease leads to destruction of the periodontium such as alveolar bone, cementum, the periodontal ligament, and gingiva. Effective treatment for periodontal tissue regeneration is important, because periodontal disease is related to several systemic diseases. However, various conventional therapies for periodontal tissue regeneration have shown limited and variable clinical outcomes. Thus, there are ongoing efforts to identify an alternative cell source, such as stem cells, for the development of new tissue engineering therapies. In this review, periodontal disease and the application of tissue engineering for periodontal tissue regeneration are discussed. In particular, adipose-derived stem cells are presented as an agent for restoring periodontal tissue defects.

Regenerative therapy using stem cells for the treatment of vocal fold wound healing and fibrosis is a very active area of research in Otolaryngology. Although modern phonosurgical methods can deal with many types of vocal fold pathology, vocal fold scar remains a clinical challenge. Trauma (e.g. vocal abuse, phonosurgery) and inflammation (e.g. laryngitis) are the two main causes of the vocal fold scarring. Several recent reviews detail the problem of vocal fold scarring and the array of possible solutions under investigation. The search for solutions includes autologous tissues, biomaterial implants, growth factors, anti-fibrotic agents and stem cells. This review focuses on emerging research on stem cells for vocal fold regeneration and our own studies of interactions between adipose-derived stem/stromal cells and vocal fold fibroblasts using an in vitro model. While clearly an opportunity, the challenging approach of treating vocal scarring using ASCs has just started. For future in vivo studies, improvements in cell viability and markers of stem-cell differentiation into normal fibroblasts are needed. The roles of stem cell-derived cytokines in paracrine signaling need to be further explored at a cellular level in vitro, and then extended to in vivo experiments.

Severe hepatic dysfunctions including hepatic cirrhosis and hepatocarcinoma are life-threatening conditions for which effective medical treatments are needed. With the only effective treatment to date being orthotropic liver transplantation, alternative approaches are needed because of the limited number of donors and the possibility of immune-rejection. One alternative is regenerative medicine, which holds promise for the development of a cell-based therapy enabling hepatic regeneration through transplantation of adipose tissue-derived mesenchymal stem cells (AT-MSCs) or hepatocyte-like cells generated from AT-MSCs. When compared with embryonic stem (ES) cells and induced pluripotent stem (iPS) cells, the use of AT-MSCs as regenerative cells would be advantageous in regard to ethical and safety issues since AT-MSCs are somatic cells and have the potential to be used without in vitro culture. These autologous cells are immuno-compatible and exhibit controlled differentiation and multi-functional abilities and do not undergo post-transplantation rejection or unwanted differentiation such as formation of teratomas. AT-MSC-based therapies may provide a novel approach for hepatic regeneration and hepatocyte differentiation and thereby support hepatic function in diseased individuals.

Stem cells are considered an ideal tool for the supply of insulin-producing cells or repairing damaged pancreatic tissues to treat diabetes mellitus, with the possibility of unlimited sources. This cell population includes embryonic, adult bone marrow, pancreatic stem cells, extra pancreatic (such as hepatic cells) and adipose-derived stem cells. Multipotent adipose tissue-derived stem cells (ADSCs) are abundant in the human body, and thus are an ideal donor source for autologous transplantation to generate insulin-producing cells. Moreover these cells are better sources than bone marrow stem cells (BMSCs) for clinical applications, owing to minimal invasive procedures, high proliferation and multi-differentiation potential. Human adipose tissue-derived stem cells (hADSCs) may thus provide an alternative stem cell source, replacing BM-MSCs or embryonic stem cells (ESCs) for future clinical use in diabetes mellitus treatment.

In addition to being a protective shield, the cornea represents two thirds of the eye's refractive power. Corneal pathology can affect one or all of the corneal layers, producing corneal opacity. Although full corneal thickness keratoplasty has been the standard procedure, the ideal strategy would be to replace only the damaged layer. Current difficulties in corneal transplantation, mainly immune rejection and shortage of organ supply, place more emphasis on the development of artificial corneas. Bioengineered corneas range from prosthetic devices that solely address the replacement of the corneal function, to tissue-engineered hydrogels that allow regeneration of the tissue. Recently, major advances in the biology of corneal stem cells have been achieved. However, the therapeutic use of these stem cell types has the disadvantage of needing an intact stem cell compartment, which is usually damaged. In addition, long ex vivo culture is needed to generate enough cell numbers for transplantation. In the near future, combination of advanced biomaterials with cells from abundant outer sources will allow advances in the field. For the former, magnetically aligned collagen is one of the most promising ones. For the latter, different cell types will be optimal: 1) for epithelial replacement: oral mucosal epithelium, ear epidermis, or bone marrow- mesenchymal stem cells, 2) for stromal regeneration: adipose-derived stem cells and 3) for endothelial replacement, the possibility of in vitro directed differentiation of adipose-derived stem cells towards endothelial cells provides an exciting new approach.