scientific and clinical evidences
Introduction: Adipose Derived Stem Cells
Mesenchymal stem cells (MSC) are multipotent adult cells capable of self-renewal and differentiation into various cell lineages.
Bone marrow (BM) MSC are currently considered the gold standard, by which newly discovered sources of MSC are compared on the basis of renewal and multipotency. Recent studies have shown that subcutaneous adipose tissue provides a clear advantage over other MSC sources due to the ease with which adipose tissue can be accessed (under local anesthesia and with minimum of patient discomfort) as well as to the ease of isolating stem cells from the harvested tissue [Casteilla et al., 2005].
Stem cell frequency is significantly higher in adipose tissue than in BM and maintenance of the proliferating ability in culture seems to be superior in ADSC compared with BM-MSC [Puissant et al., 2005]. ADSC are isolated through an initial enzymatic digestion of harvested adipose tissue, that yields a mixture of stromal and vascular cells (preadipocytes, fibroblasts, vascular smooth muscle cells, endothelial cells, resident monocytes/macrophages, lymphocytes and ADSC ) referred to as stromal-vascular fraction (SVF) [Zuk et al., 2001]. SVF is a rich source of pluripotent ADSC [8, 9], which were first identified by Zuk and named processed lipoaspirate (PLA) cells [8, 10]. The selection of ADSC out of SVF is based on their physical adherence to plastic tissue culture dishes.
Morphologically, ADSC are fibroblast-like cells and preserve their shape after in vitro expansion [8, 12, 13]. Minimal criteria have been proposed to define MSC -and by similarity, ADSC- by the Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy . These are: plastic adherence ability; tripotential mesodermal differentiation potency into osteoblasts, chondrocytes, and adipocytes; immunomodulatory capability . Several groups demonstrated ADSC multipotency showing differentiation toward various cells derived from ectoderm (epithelial cells and neurons), mesoderm (connective stroma, cartilage, fat and bone cells) and endoderm (muscle cells, gut epithelial cells and lung cells) [10, 15, 19-21].
Based on beta-galactosidase activity, ADSC have been shown to exhibit telomerase activity similar to BM-MSC that, although lower than that in cancer cell lines, indicates maintenance of the capacity for self-renewal and proliferation even after transplantation. A recent study investigated the fundamental changes of ADSC in long-term culture by studying the morphological feature, growth kinetic, surface marker expressions, expression level of the senescence-associated genes, cell cycle distribution and ß-galactosidase activity. The morphology of ADSC in long-term culture showed the manifestation of senescent feature at P15 and P20 and all the results showed that culture till 10 in vitro passages is safe (22391697).
ADSC and immunomodulation and clinical implications
An emerging body of evidence shows that MSC possess intrinsic immunomodulatory properties and immunoprivileged characteristics and can modulate a wide range of target cells within the innate and adaptative arms of the immune system (19172693).
The mechanism underlying MSC inhibitory effect is not fully elucidated and is likely to be multifactorial and to result from the communication between various immune cells and cytokine generation. Therefore, a combination of the paracrine activity of MSC and direct cell-cell contact is at the basis of their immunomodulatory effects.
Besides being immunosuppressive, ADSC are also immunoprivileged: they have low immunogenicity due to low expression of human leukocyte antigen (HLA) class I and no expression of class II molecules, as demonstrated by flow cytometry.
The lack of HLA-DR expression and the above described immunosuppressive properties of ADSC make them suitable even for allogenic transplantation procedures, irrespective of MHC incompatibility . Because of the great immunomodulatory effects of MSC in vivo and in vitro and since the first report by Le Blanc et al. , MSC have been mainly used for treating or preventing acute graft versus host disease (GVHD) during allogeneic hematopoietic stem cell (HSC) transplantation. The efficiency of such therapy is greatest in liver and gut GVHD and in children (17910665). On the whole, their immunomodulatory function as well as the approved clinical trials, suggest that these cells are efficient for treatment for several classes of autoimmune diseases and that their application is safe .
ADSC differentiation and clinical applications
The broad range of clinical applications for ADSC largely depends on their potential for differentiation and on their ability to migrate and to recruit endogenous stem cells from the niches. There are numerous scientific publications demonstrating that ADSC possess the potential to differentiate towards a variety of cell lineages both in vitro and in vivo:
ADSC capability to differentiate towards adipogenic lineages has implications for breast soft tissue reconstruction after tumor surgery, for breast cancer, breast asymmetry and soft tissue and subdermal defects, after trauma, surgery or burn injury. As the differentiation of ADSC into adipocytes is not in any doubt and as there is a strong demand in reconstructive and cosmetic surgery, progression of related clinical treatments and trials is further advanced than for other differentiation lineages.
ADSC can be used for skeletal regeneration of inherited and tumor- or trauma-induced bone defects, thanks to their osteogenic differentiation. Following osteogenic differentiation, ADSC can acquire even bone cell-like functional properties, such as responsiveness to fluid shear stress [16411823) and increase their expression of both alkaline phosphatase and mechanosensitive genes, such as osteopontin, collagen type I1, and COX-2 after mechanical loading.
ADSC chondrogenic commitment is relevant for joint and disc defects repair and for plastic reconstruction of ear and nose defects.
Given their myogenic and cardiomyogenic properties, ADSC are useful for muscle reconstruction after trauma and surgery, dystrophic muscle disorders, heart muscle regeneration, functional improvement after myocardial infarction or heart failure. Cultured ADSC have the potential for differentiation into a cardiomyocyte-like phenotype with specific cardiac marker gene expression and pacemaker activity . However, the myogenic potential of ADSC may be harvested in the treatment of Duchenne muscular dystrophy (DMD), an inherited genetic disorder characterized by progressive degeneration of skeletal muscle. In vivo murine studies have shown that the implantation of ADSC into dystrophin-deficient, immunocompetent mice resulted in restoration of dystrophin expression, both in the muscle at the site of injection and in adjacent muscles over the long-term .
ADSC have been shown as useful for neovascularization and, therefore, for ischemic diseases.
As far as the differentiation into cells of the mesodermal lineages and regeneration of mesodermal tissues is concerned, ADSC can differentiate as well as into tenogenic and periodontogenic lineages .
Given their ability to differentiate both morphologically and functionally into neurons, they are currently under investigation for neurological diseases, for brain injury, stroke, neuronal protection and peripheral nerve injury.
Finally, it has been shown that ADSC can differentiate into endoderm lineage cells. Several reports have shown that ADSC have the potential to differentiate into hepatocytes as indicated by the presence of HGF and FGF-1 and 4 . ADSC can be induced to become not only hepatic cells, critical for chronic liver failure, hepatic regeneration or even hepatocyte transplantation, but also pancreatic/endocrine insulin-secreting cells, relevant for type 1 diabetes mellitus. Timper et al.  were successful in differentiating human ADSC into cells with a pancreatic endocrine phenotype using the differentiation factors activin-A, exendin-4, HGF, and pentagastrin. The differentiated cells expressed the endocrine pancreatic hormones insulin, glucagon, and somatostatin.
The first clinical trials with SVF cells and ADSC are ongoing, in the form of:
- phase I (e.g. myocardial infarction, skin ulcer or graft versus host disease),
- phase II (e.g. in rectovaginal fistula),
- phase III (e.g. enterocutaneous fistula) and
- phase IV (e.g. breast reconstruction) studies (for details, see section below).
ADSC mechanism of action
The potential benefits of ADSC are promising for regenerative medicine because they have several advantages: ability to continue proliferating after transplantation , to differentiate into endothelial cells and to induce neovascularization  and to release angiogenic and anti-apoptotic growth factors . In terms of the proposed mechanisms for regeneration of ADSC, because they are known to differentiate into various cell types, it was thought initially that the mechanism involved engraftment and differentiation into injured tissue. Interestingly, a robust engraftment into the target tissue is not a requisite for ADSC to mediate their clinical effects. Only a minority (often < 1%) of intravenously infused MSC reaches the damaged tissue and disappears after few days (19172693). Despite this low level of engraftment, ADSC mediate their therapeutic effects through paracrine actions rather than transdifferentiation, stimulating proliferation and differentiation of resident progenitor cells (10102814- 17700588).
A number of papers have described the secretory profiles of pre-adipocytes, ADSC, or adipose tissue, which were determined using Enzyme Linked Immunoabsorbent Assays (ELISA) or related techniques. ADSC secrete high levels of epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), keratinocyte growth factor (KGF), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), transforming growth factor-beta (TGF-β), insulin-like growth factor (IGF), and brain-derived neurotrophic factor (BDNF) [40-45]. They also secrete cytokines such as Flt-3 ligand, granulocyte colony stimulating factor (G-CSF), granulocyte/macrophage colony stimulating factor (GM-CSF), macrophage colony stimulating factor (M-CSF), interleukin-6 (IL-6), interleukin-7 (IL-7), interleukin-8 (IL-8), interleukin-11 (IL-11), interleukin-12 (IL-12), leukemia inhibitory factor (LIF), and tumor necrosis factor-alpha (TNF-α) [43, 46]. These angiogenic and anti-apoptotic growth factors are secreted in bioactive levels by ADSC.
Therefore, the capacity of ADSC to exert a potent tissue protective effect by several mechanisms (i.e., immunoprotection and paracrine stimulation) suggest that they might trigger endogenous mechanisms of regeneration that self-sustain, accordingly to the input they receive from the transplanted tissue, and that survive after cells disappearance.
To date, any studies suggesting that hADSC have a tumorigenic potential are either inconclusive or have been retracted [49, 50] (+20631079), due to cross-contamination of the examined hADSC cultures with immortalized tumor cell lines. In a recent study culture-expanded hADSC were applied to immunosuppressed mice. At one year, animals were no different in weight nor life span from controls and showed no signs of tumorigenesis . The same result on the safety of ADSC systemic administration had been obtained by Ra and coworkers: to test the toxicity of hADSC, different doses of hADSC were injected intravenously into immunodeficient mice, and the mice were observed for 13 weeks. Even at the highest cell dose (2.5×108 cells/kg body weight), the SCID mice were viable and had no side effects. A tumorigenicity test was performed also in Balb/c-nu nude mice for 26 weeks and again no evidence of tumor development was found (21303266).
To conclude, it must be recognized that the risk of neoplasia from stem cells, particularly MSC, has long been managed in clinical trial development. Ongoing studies will add substantially to the database of safety information (sustained ventricular arrhythmias, ectopic tissue formation, or sudden unexpected death). Very importantly, phase I clinical trials have already specifically monitored for unwanted tissue formation. It has to be noted, however, that patients with increased oncological risk due to underlying comorbidities or to ongoing immunosoppression treatments have been excluded by most trial designs and that, for the moment, most trial have a short follow up (19958962, 21415390). The evidence that so far in a quite large cohort of patients (more than 700) with hematologic tumors or non-neoplastic disease, exposed to MSC therapy, none has developed new neoplasias even on long-term follow-up, can be taken as a reasonable proof of the safety of the procedure. In this regard, it is worth noting that there is an interest on the exploitation of the well established tropism of MSC for the tumor microenvironment as a “Trojan horse” to deliver anti-cancer agents and this use is already approaching the “bed side” for treatment of neuroblastoma .
In this frame, Bioscience Institute developed LIPOSkill®, a technology that allows isolation, characterization and in vitro expansion of autologous ADSC, starting from a fat tissue sample. Once expanded, cells will be released for treatment as a suspension in a hyaluronic acid containing solution. Briefly, LIPOSkill® is obtained from about 10 ml of fat harvested using surgical liposuction or in one outpatient session. After collection, the sample is placed in an isothermal container which guarantees the best security, temperature and pressure conditions for the shipment of biological material.
The kit is collected by a specialised delivery service and delivered to Bioscience Institute in a very short time, respecting the necessary procedures required by biological material. Upon arrival, biologists at Bioscience Institute process the sample to isolate and expand a homogeneous population of ADSC according to the maximum biological security conditions.
After expansion, cells can either undergo programmed freezing in order to interrupt senescence and be ready in case of future need or be released for treatment.
List of clinical trialsSource: Clinicaltrials.gov
NCT01440699: Study of Allogenic Adipose-derived Stem Cells in Crohn's Fistula, sponsored by Anterogen Co., Ltd.
NCT01314092: Clinical Trials of Autologous Cultured Adipose-derived Stem Cells (ANTG-ASC) on Complex Fistula, sponsored by Anterogen Co., Ltd.
NCT00715546: Autologous Adipose-Derived Stem Cell Transplantation in Patients With Lipodystrophy, sponsored by Irmandade Santa Casa de Misericórdia de Porto Alegre.
NCT00992485: Safety and Efficacy Study of Autologous Cultured Adipose -Derived Stem Cells for the Crohn's Fistula, sponsored by Anterogen Co., Ltd.
NCT01011686: Safety Study of Autologous Cultured Adipose -Derived Stem Cells for the Fecal Incontinence, sponsored by Anterogen Co., Ltd.
NCT00703612: Safety and Efficacy of autologous Adipose derived stem cells transplantation in Type 2 diabetics, sponsored by Adistem Ltd.
NCT01011244: Safety and Efficacy Study of Autologous Cultured Adipose -Derived Stem Cells for the Crohn's Fistula, sponsored by Anterogen Co., Ltd.
NCT00703599: Safety and Efficacy of Autologous Adipose-Derived Stem Cell Transplantation in Patients With Type 1 Diabetes, sponsored by Adistem Ltd.
NCT01378390 : Safety and Efficacy of Adipose-Derived Stem Cells to Treat Complex Perianal Fistulas Patients With Crohn's Disease, sponsored by Cellerix.
NCT01372969: Study to Assess the Safety and Efficacy of Expanded Allogenic Adipose-derived Stem Cells (eASCs) (Cx601), for Treatment of Complex Perianal Fistulas in Perianal Crohn's Disease, sponsored by Cellerix.
NCT00442806: Randomized Clinical Trial of Adipose-Derived Stem Cells in the Treatment of Pts With ST-elevation Myocardial Infarction, sponsored by Cytori Therapeutics.
NCT00999115: Allogenic Stem Cells Derived From Lipoaspirates for the Treatment of Recto-vaginal Fistulas Associated to Crohn`s Disease (ALOREVA), sponsored by Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz.
NCT01314079: Follow-up Study of Autologous Cultured Adipose-derived Stem Cells for the Crohn's Fistula, sponsored by Anterogen Co., Ltd.
NCT00475410: Efficacy and Safety of Adipose Stem Cells to Treat Complex Perianal Fistulas Not Associated to Crohn´s Disease, sponsored by Cellerix.
NCT00426868: A Randomized Clinical Trial of Adipose-derived Stem Cells in Treatment of Non Revascularizable Ischemic Myocardium, sponsored by Cytori Therapeutics.
NCT01020825: Long-term Safety and Efficacy of Adipose-derived Stem Cells to Treat Complex Perianal Fistulas in Patients Participating in the FATT-1 Randomized Controlled Trial, sponsored by Cellerix.
NCT00115466: Autologous Stem Cells Derived From Lipoaspirates for the Non-Surgical Treatment of Complex Perianal Fistula, sponsored by Cellerix.
NCT01257776: Human Adipose Derived Mesenchymal Stem Cells for Critical Limb Ischemia in Diabetic Patients, sponsored by Fundacion Progreso y Salud, Spain.
NCT01274975: Autologous Adipose Derived MSCs Transplantation in Patient With Spinal Cord Injury, sponsored by RNL Bio Company Ltd.
NCT01157650: Treatment of Fistulous Crohn's Disease by Implant of Autologous Mesenchymal Stem Cells Derived From Adipose Tissue, sponsored by Instituto Cientifico y Tecnologico de Navarra, Universidad de Navarra.
NCT01300598: Autologous Adipose Tissue Derived Mesenchymal Stem Cells Transplantation in Patient With Degenerative Arthritis, sponsored by RNL Bio Company Ltd.
NCT01302015: Autologous Adipose Tissue Derived Mesenchymal Stem Cells Transplantation in Patient With Buerger's Disease, sponsored by RNL Bio Company Ltd.
NCT00992147: Safety and Efficacy of Autologous Cultured Adipocytes in Patient With Depressed Scar, sponsored by Anterogen Co., Ltd.
NCT01309061: The Effect of Human Adipose Tissue-derived MSCs in Romberg's Disease, sponsored by RNL Bio Company Ltd.
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