1 Background

Regenerative medicine is a relatively new branch of science that aims to replace aged, damaged, and disease- or trauma-affected tissues and organs, and to stimulate organismal regenerative potential.

Stem cell therapy involves several mechanisms of action. One is direct replacement of damaged cells and tissues [1]. Another is a paracrine mechanism that involves modulation of the microenvironment, activation of the native immunity, anti-inflammatory effect and prevention of fibrosis development, pain relief through the secretion of cytokines, regulation of cell death, and immunomodulatory effect [2, 3]. Stem cell therapy is considered one of the most promising and highly effective treatment methods for several inflammatory diseases, infectious diseases, non-communicable diseases, cancer, age-related pathologies, pediatric diseases and rejuvenation [4,5,6].

Despite this, stem cell therapy is still not widespread and is even forbidden in some countries. Based on available data, no more than 15 allogeneic mesenchymal stem cell (MSC) products have been approved worldwide [7]. Implementation rates of stem-cell-based therapeutic products remain low, but they have been gradually increasing; as of 17 August 2022, twenty-four cellular and gene therapy products have been licensed by the Office of Tissues and Advanced Therapies (USA) [8]. Medical tourism to seek stem-cell-based therapies has increased significantly despite the small number of clinical studies and poor evidence base for such therapies [7, 9].

Initially MSCs were first found in bone marrow in 1976. It has been shown that MSCs, which are multipotent, can differentiate into mesenchymal, endodermal, and ectodermal cell lines [10]. Bone marrow is the gold-standard source of MSCs [11]. The most common harvesting site for bone marrow is the iliac crest, followed by the proximal femur [12]. However, bone marrow aspiration has significant drawbacks due to its high invasiveness and low MSCs yield [13]. Even MSCs harvested from different bones of the same individual differ in terms of their regenerative potential and cell concentration, and their effects vary between in-vivo and in-vitro settings [14]. Bone marrow biopsy is poorly tolerated by patients because of post-procedure pain, and most patients experience anxiety before and during the procedure, even in the case of experienced bone marrow donors [15, 16]. Owing to these limitations, alternative MSC donor sites and new approaches are in high demand. Connective tissue and stromal components of inner organs are graft-rich sources for MSCs isolation. One of these is adipose tissue, which is in abundance in a human body. The high proliferation and differentiation capacity of adipose-derived stem cells (ADSCs) and their more accessible donor sites make them a more promising and less invasive alternative to bone-marrow MSCs (BM-MSCs) for stem-cell-based therapies [17]. ADSCs and BM-MSCs have similar characteristics in terms of their morphology, properties, and receptors[18]. There are also other sources of adult tissue-derived MSC such as peripheral blood, endometrium, tooth pulp, and breast milk [19]. Umbilical cord, cord blood, placenta and amniotic fluid are the neonatal sources of stem cells [20]. Adult and neonatal stem cells have various clinical applications and their own advantages and disadvantages. Neonatal stem cells have higher proliferative capacity, potential growth by multi-layering due to the absence of contact inhibition, no senescence over passaging and lower immunogenicity, and higher immunosuppressive capacity [20]. Despite possessing better immunological properties, neonatal stem cells have several disadvantages that limit their clinical application such as low cell amount in a single cord blood unit, single time collection, high storage cost etc. [21].

In most circumstances, only the allogeneic application of neonatal stem cells is possible, while BM-MSCs, ADSCs and peripheral blood stem cells can also be used in autologous settings, which significantly facilitates ethical issues, prevents infections from spreading, and provides a limitless source of cells [22]. Moreover, BM-MSCs are not immune-privileged and have immunogenic potential in allogeneic settings [23]. Two strategies exist for prolonging their persistence and improving the efficacy of stem cell therapy: modifying the host immune system response or modifying the antigen properties of MSCs [24].

The range of application of stem cells-based treatment in clinical medicine expands every year, especially adipose tissue as one of the favorable sources of stem cells found a broad application in tissues engineering [25, 26]. This review aims to summarize current understandings of ADSC biology, to discuss the latest ADSC-based experimental studies and clinical trials, and to highlight the current advantages and limitations of using ADSCs in medicine.

A systematic search in the PubMed and Scopus database was conducted on 12 October 2023 for all studies including ADSCs, BM-MSCs and MSCs. Original articles, review articles, meta-analysis, clinical cases and case series written in English were selected for review. The search strategy included usage of the following terms: “adipose-derived stem cells”, “fat-derived stem cells”, “bone marrow-derived stem cells”, “mesenchymal stem cells” and their synonyms. Retrieved articles, relative to the review topic, were stored in a database and duplicates were removed.

2 Main text

2.1 Status of research regarding regenerative medicine using ADSCs

ADSCs were first retrieved from lipoaspirates by Zuk et al. in 2001 [27]. While BM-MSCs were historically discovered earlier than ADSCs, their clinical application is sometimes limited. This is why an alternative source of MSCs is required. One of them is ADSCs that have been intensively studied worldwide owing to their relative ease of isolation, few ethical considerations, non-invasive harvesting procedure, good culturing properties, and promising results in in-vitro and in-vivo research.

Medical stem cell therapy is flourishing worldwide; however, patients sometimes have unsubstantiated expectations regarding stem cell therapy. Sometimes, stem cell treatment is provided without proper indications and has life-threatening consequences [28]. The high cost of treatment, low quality, long waiting times, jurisdictional legal restrictions, inability to participate in clinical trials, and lack of access to unapproved treatments lead patients to engage in stem cell tourism. The leaders in international MSC tourism are the USA, China, India, Thailand, and Mexico [29].

In Japan, in addition to laws governing clinical trials conducted under the International Conference on Harmonisation – Good Clinical Practice and the requirement for the approval of regenerative medical products (Pharmaceutical and Medical Device Act), the Act on the Safety of Regenerative Medicine governs the implementation of regenerative medicine in clinical trials or as a treatment. Due to the Regenerative Medicine Act all the procedures were classified into risk categories (high, intermediate and low risk, which are Class I, II and III respectively), among which treatment and research using ADSCs are being conducted in various clinical departments, including the orthopedic and dental fields [30].

Around the world, stem cell therapies, including those using ADSCs, are offered in clinical practice, with the main clinical indications being multiple sclerosis, cellular therapy of cornea injuries, chronic pulmonary disease, rejuvenation, Parkinson's disease, bone and soft tissues augmentation and regeneration which were destroyed due periodontitis, stroke therapy, severe spinal cord injury, cerebral palsy, chronic wound healing, autism, amyotrophic latent arteriosclerosis, Alzheimer's disease, and inflammatory joints disease [31].

A search of “adipose-derived stem cells” on www.clinicaltrials.gov found that more than 394 clinical trials using ADSCs have been conducted worldwide, 132 of which have already been completed. In clinical trials, ADSCs have been used for face rejuvenation, keloid treatment, reconstructive surgery, alopecia treatment, arthritis therapy, periodontal therapy, diabetic wound healing, and many other purposes.

2.2 Biology of adipose tissue

Adipose tissue is a connective tissue with special properties. Approximately 20–25% percent of a healthy individual’s weight is adipose tissue. Based on morphological differences, adipocytes were distributed into white, brown and bright (beige) adipocytes. Depending on its location, adipose tissue is classified into subcutaneous (located under the skin) or visceral (around inner organs) fat. White adipocytes are found in white adipose tissue (WAT), and cell shape varies from spherical to oval or polyhedral. Almost the entire cell volume is occupied by a unilocular lipid droplet which occupied the central part of an adipocyte and flattens to the periphery nucleus. The adipocyte`s lipid droplets are lost on a histological section during the traditional way of tissues preparation, which gives WAT a thin polygonal mesh appearance [32, 33]. Visceral adipose tissue (VAT) presented as abdominal viscera, mesenterium and omentum, has completely different qualities compared to WAT. Adipocytes type, their secretome, endocrine regulation, proliferation rate, lipolytic activity, sensitivity to insulin and other hormones differ between subcutaneous WAT and visceral fat. Macrophages are more prevalent in VAT compared with subcutaneous WAT [34].

Brown adipose tissue is common in newborns and located in the neck, back and shoulder areas. With maturation, brown fat scatters around the body. In adults it is located around the neck and inner organs such as the kidneys, adrenal glands, aorta and mediastinum. Brown adipocytes are much smaller compared to white and beige adipocytes, and their lipids are distributed into numerous lipid droplets, with their nucleus located at the cell center. These cells are abundant in mitochondria, with a brown appearance. The major function of these cells is to produce heat. There are two types of brown adipocytes: high- and low-thermogenic adipocytes [35].

Beige adipocytes are a recently discovered type of brown adipocyte located in subcutaneous fat depots, such as the inguinal and anterior subcutaneous WAT; however, a small number can also be found in VAT [36]. Beige adipocytes have a multilocular morphology. Properties, cultural and functional differences of white, brown and beige adipocytes summarized in Table 1.

Table 1 Morphological, functional, cultural differences of white, brown and beige adipocytes in an adult human
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Similar to every connective tissue, adipose tissue presented as cells surrounded by an extracellular matrix. Cells percentage in adipose tissue is significantly prevail under the extracellular matrix component. Adipocyte is a minimal structural and functional unit of adipose tissue. Besides adipocytes, adipose tissue also consists of preadipocytes, fibroblasts, capillary endothelial cells, macrophages, and stem cells, all of which form the stromal vascular fraction (SVF) that supports, supplies, and protect adipocytes [36]. Adipose tissue has a good blood supply and is innervated by unmyelinated nerves [37].

In mammals, adipose tissue has the following important functions: energy storage, hormone secretion, metabolism, protection, and thermogenesis. In recent years, adipose tissue has been considered as a powerful endocrine organ because it produces several hormones such as estrogen, leptin, adiponectin, resistin, and biologically active substances such as TNF, IL-6, IL-1, CCL2, MCP1, PAI-1, and complement factors [38, 39].

SVF is one of the adipose tissue components that is a mixture of cells contained within adipocytes that is traditionally isolated by enzymatic digestion. After adipocytes extraction, connective tissue and blood from lipoaspirate, come the SVF, a mix including MSC, endothelial precursor, T-reg, adipose tissue macrophages, smooth muscle cells, pericytes and preadipocytes [40, 41].

2.3 Adipose tissue as a source of MSC

WAT is a huge source of MSCs with superior culturing properties. In humans that WAT has an abundance of CD-34+ -cells, immunohistochemical analysis has confirmed that CD-34+ cells are evenly distributed among white adipocytes [10]. It has been shown that about 5 × 105 stem cells can be isolated from a few milligrams of adipose tissue with the possibility of continuously culturing in vitro for up to one month without cell passaging [42]. Adipose tissue is a prospective source of MSCs owing to variable donor sites, the large quantity of biological sources from deceased donors, and routine deceased-donor workups [43, 44]. Studies have shown that WAT harvested from the abdomen of deceased, research-consenting donors indicated that the total nucleated cell count was even higher than that in living donors, and the morphology and functional properties (growth potential, gene expression level, and differentiation ability) of the cell culture were similar [43, 44]. However, changes in the properties and biology of adipose tissue in obese individuals are a general health condition [39, 45,46,47]. Isolated ADSCs from VAT and subcutaneous WAT had no differences in morphology and had the same expression of CD antigens. However, the growth rate of subcutaneous WAT ADSCs is 1.75 faster than ADSCs isolated from VAT also ADSCs were different in terms of angiogenic and inflammatory cytokines level. ADSCs from subcutaneous WAT have significantly lower concentrations of chitinase 3-like 1, IL-1β, EGF, MCP-1, Cystatin C, IL-6, IL-8, Pentraxin 3, TGF-β, plasminogen activator urokinase receptor and TNF-α [48].

There are three main criteria for ADSCs. Firstly, MSCs must have adherent growth; trilineage mesenchymal differentiation (adipocytes, osteoblasts, and chondroblasts). Secondly, ADSCs must express surface specific antigens such as expressing MSCs markers like CD44, CD105, CD90, and CD73, which are progenitors in subcutaneous WAT, and their phenotype is similar to BM-MSCs. Thirdly, ADSCs do not express the HLA-DR protein or MHC Class I molecules, which enable the possibility of allogeneic transplantation [49].

Some scientists considered that ADSCs to be immune-privileged cells [41]. The concept of immune privilege means that some biological grafts can survive in the recipient’s body for a certain time without triggering a graft-versus-host response or large-scale destructive inflammation in the place of application [50]. However, other studies have shown that MSCs are not completely immune-privileged, due to the triggering of both humoral and cellular immune responses in vivo, which depends on the microenvironment [24]. For example, the second transplantation of allogeneic MSCs from the same donor in mice resulted in accelerated rejection of cells, which attests to the formation of T-cell memory [51]. It was reported that ADSCs have superior immunomodulatory action because of the less MHC class II expression that makes them a prospective graft material for allogenic treatment [52]. Allogeneic ADSCs have immunological potential and can trigger graft rejection and inflammation in the recipient’s body. Introducing the human cytomegalovirus US2/US3 gene into ADSCs reduced ADSC immunogenicity and graft rejection by decreasing MHC I protein expression [53]. This method is promising for obtaining the same effect after transplantation of allogeneic ADSCs as autogenetic ADSCs [53]. Was reported that immunomodulatory effect related to the regenerative capacity has been increasing [52]. Moreover, it was shown that MSCs are able to produce molecules which have antimicrobial and analgetic properties, making them a prospective therapeutic agent against cytokine storm- infections [54, 55].

Several studies also indicate promising clinical results with brown adipocyte transplantation for the treatment of diabetes and obesity [56]. In experimental research, brown adipocyte transplantation improved the regulation of adipose tissue and glucose homeostasis as well as insulin resistance [57]. However, the specific mechanisms behind these effects have not yet been discovered [35].

2.4 Mechanism of ADSCs action

ADSCs therapy is based on direct replacement of damaged cells with differentiated ADSCs or modification of local paracrine signaling by extracellular vesicles (see Fig. 1). Studies report that under different conditions in vitro, ADSCs can differentiate into ectodermal, mesodermal, and endodermal progenitors [11, 17, 58, 59]. However, only several of these studies reported a successful result in in-vivo studies or clinical trials. Differentiation of ADSCs in vivo is challenging due to poor cell survival, mostly because of the transplantation of cells into organs with a hypoxic environment. However, compared with mature adipocytes, ADSCs have higher survival rates because of less sensitivity to ischemia and secretion of angiogenic factors that stimulate local angiogenesis [60].

Fig. 1
figure 1

Possible mechanism of ADSCs action via direct cell replacement and paracrine signaling

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Studies reported the successful usage of ADSCs in endometrial injury treatment. ADSCs underwent differentiation into mature endometrial epithelial cells, which resulted in endometrial structure and function regeneration [61]. However, most of studies are limited to the in vitro demonstration of ADSCs differentiation such as differentiation of ADSCs into insulin-producing cells, cells with hepatocytic function, osteocytes, adipocytes etc. [58, 60, 62, 63]. Nowadays, clinical translation of ADSC-based therapy for a direct cell’s replacement is difficult since most of the mechanisms for stem cells differentiation in the in vivo setting remains unclear. Such treatment might possibly result in the initial stages of cancer development and other adverse results [64]. ADSCs under inflammation regulate the inflammatory stimuli, triggering the synthesis of pro-angiogenic factors such as VEGF-A, hepatocyte growth factors, and IGF-1 as well as that of hematopoietic cytokines such as macrophage-colony stimulating factor, granulocyte-colony stimulating factor, IL-6, TNF-α [65].

Another more promising implication of ADSCs is via regulation of local tissue homeostasis. ADSCs possess unique paracrine characteristics. It is realized through extracellular vesicles (EVs) which contain products of cell secretion and transport it to the target cells to regulate cell function and change their phenotype via cell signaling. EVs are secreted by many different cell types, including ADSCs. They contain microRNA, mRNA, lipids, and proteins, and are classified as microvesicles (50–1000 nm in size) and exosomes (30–100 nm)[66, 67].

Recently, several promising results of treatment using isolated from ADSCs exosomes were shown. Exosomes of ADSCs contain numerous growths regulating cytokines that enhance recovery of damaged tissue and growth factors that mediate tissue regeneration. These growth factors are: basic fibroblast growth factor, VEGF-A, insulin-like growth factor 1, hepatocyte growth factors, and transforming growth factor, brain-derived neurotrophic factor, nerve growth factor, and glial-derived neurotrophic factor, matrix metalloproteinase- (MMP-) 3 and MMP-9 [68, 69].

ADSCs exosomes treatment showed promising results in therapy of neurological diseases, liver fibrosis, myocardial ischemic injuries, endocrine diseases, bone and skin regeneration. Isolated ADSCs exosomes were used for the treatment of ischemic brain injury. They reduced brain ischemia caused by the microglial polarization, which was caused by the delivery of microRNA to inhibit the expression of signal transducers and activators of transcription 1 and phosphatase and tensin homolog deleted on chromosome ten (PTEN) [70]. Metastasis-associated lung adenocarcinoma transcript 1 was identified as one of the ADSCs exosomes component that contributes to increased neuronal survival and proliferation in traumatic brain injury or other neurodegenerative diseases [71, 72]. Mouse ADSC EVs reduced apoptosis of motor neurons of in vitro amyotrophic lateral sclerosis model under the condition of oxidative stress alteration [73].

Further, exosomes of ADSCs decrease hepatic fibrosis development through the suppression of autophagy, PI3K/AKT/mTOR,,TGF-β/smad, Wnt/β-catenin, LPS/TLR4, EMT/ERK1, PPAR-γ, NF-κB signaling pathways and by the changing of lipid metabolism through regulation of choline metabolism [74, 75]. ADSCs exosomes also suppress the proliferation rate of stellate cells through stimulation of apoptosis and arrest of G1 phase of the cell cycle, and through the inhibition of profibrogenic proteins and epithelio-mesenchymal transition [76]. ADSCs exosome therapy reduced liver damage by downregulation of collagen I, vimentin, α-SMA and fibronectin in liver via selectively transfer of miR-181-5p to affected hepatocytes [77].

Exosomes isolated from ADSCs are used for the therapy of diabetes mellitus associated erectile dysfunction. They enhance the secretion of the endothelial markers and downregulate caspase-3 after the operation [78]. ADSCs exosomes activate functional recovery and activate endogenous repair mechanisms of corpus cavernosum via micro RNA 126, 130a and 132 that provides angiogenesis and restore erectile function, and inhibit fibrosis in corpus cavernosum by antifibrotic properties of micro RNA-let7b and c [79]. Zhao et al. showed that ADSCs exosomes-based treatment induces endometrial regeneration and fertility restoration by collagen remodeling and enhancement of integrin-β3, LIF, and VEGF expression [74]. EV isolated from human ADSCs increase wound healing and restore the function and prevent scar formation via activation of PI3K/AKT pathway in sebocytes on a murine model [80].

However, ADSCs and their exosomes have very variable biological properties and cytokine content, even if they were harvested from the SCAT of the same donor but from a different anatomical location. Thus, the thigh fat had a significantly higher cytokines profile except for IL-1β and IL-6, compared with abdominal and chin sites [81]. Nowadays, standardised issue of ADSC-based therapy, that determine their mechanism of action, is one of a several major limitations of its clinical translation.

2.5 Factors impacting the clinical effectiveness of ADSCs treatment

The result of stem cell treatment depends on the general health of the cell donor. Thus, in patients with diabetes mellitus, type II ADSCs exhibit impaired viability and proliferation rate, mitochondrial dysfunction, senescence phenotype, impaired glucose homeostasis, and insulin sensitivity. Significantly low secretion of VEGF, adiponectin, and CXCL-12, in the background of hypo concentration of leptin, were observed among type-II ADSC samples [82]. General systemic diseases lead to disturbances in the function and morphology of ADSCs and reduce their therapeutic properties.

Co-transplantation of ADSCs and platelet-rich plasma (PRP) resulted in significantly increased alveolar bone and gingiva regeneration [83, 84]. Moreover, PRP activates ADSCs by increasing cytokines and growth factors production, and a fibrin network can be used as a scaffold for the stem cells and to create a conducive microenvironment that increases stemness and prolongs cellular survival rate and duration [83, 85, 86]. Mechanical tension significantly enhances osteoblastic ADSCs differentiation; however, the mitotic activity of ADSCs is not affected by mechanical tension [85]. Li et al. showed that pretreatment of freshly isolated ADSCs with thymosin beta 4 (Tβ) upregulates the expression of genes associated with cell division, decrease cells doubling time and apoptosis [87].

In reconstructive surgery, transplantation of ADSCs alone for regenerative purposes is not as effective as co-transplantation with a composition of different cells to create a favorable environment for revascularization, preventing graft resorption and necrosis. In particular, transplantation of ADSCs, adipocytes, and endothelial cells implanted into the extracellular matrix has shown a higher cellular survival rate and volume maintenance when compared to non-prevascularized control grafts [86].

The injection of ADSCs along with intraoral administration of sildenafil citrate, which enhances blood supply and NO synthesis in animal models, significantly improves the healing rate after colon anastomosis and better reduces inflammation when compared with ADSCs alone [88]. For promoting hair growth ADSCs pretreated with bee venom is reported to increase the release of fibroblast -1 and -6, endothelial and platelet growth factors and enhancement of cells migration [89].

The actions of ADSCs are determined by their environment. Human ADSCs transferred to non-inflamed mouse lungs resulted in development of mild low-grade inflammation, which can be associated with apoptotic graft or heterotransplant clearance. T-cells that produce IFNγ can activate the immune response to efferocytosis, thus altering lung homeostasis [90]. The combination of Shilajit (a herbomineral natural substance) and an alginate hydrogel environment induced osteogenic differentiation of ADSCs into osteoblasts in a short period of time [91]. Thus, a proper microenvironment can significantly enhance the outcome of ADSCs clinical applications. There are still many concerns about safety of ADSCs therapy, thus, EV from ADSCs showed suppression of breast cancer tumor growth meanwhile the components of cell growth medium had an opposite effect of a tumor [92].

2.6 Standardization of ADSCs

The translation of novel findings in stem cell therapy to clinical practice has been discouragingly limited and ambiguous, with the effectiveness of some forms of stem cell therapies remaining poorly supported by evidence. The main problem that limits the clinical application of stem cells, in addition to many other biological medical products, is poor standardization and a lack of comprehensive guidelines [93]. Standardization of biological grafts is necessary because it offers an opportunity to compare research outcomes, which leads to the optimization of ADSC-based treatment.

It is impossible to effectively translate the results of basic research to clinical settings due to differences in cell origins, cultivation conditions, obtainment methods, and the number of cell passages. Tragoonlugkana et al. showed that cell culture plates coated with platelet lysate significantly increased properties of ADSCs such as adhesion, proliferation speed and growth as well as the cells’ viability [94]. Thus, the same method of adipose tissue harvesting, but used by different commercial systems, influences the cellular content and cytokine secretion of ADSCs [95]. Distinctive changes in gene expression have been observed after a 48-h ADSCs cultivation period. Regulatory genes are involved in cell morphogenesis and metabolism, cell-to-substrate adhesion, glycoprotein metabolic processes, and regulation of fiber molecular structure organization. Downregulated genes were those involved in cell proliferation, differentiation, and transformation [96].

Cultural, biological, and functional properties of ADSCs depend on the anatomical location of fat, age, gender, and BMI of patients [97,98,99]. It is not yet clear whether isolated cells are actually ADSCs or what types of cells they are able to generate. Researchers agree that not all MSCs have identical characteristics, which can depend on the patient’s age, donor site, isolation technique, and growth [100]. Close attention should also be paid to the origin of the allogeneic graft, since several studies have underlined that donor age, sex, tissue source, and method of isolation have an effect on cellular and molecular variability [101, 102]. Another problem is the safety of the graft and its possibility of being infected with diverse latent viruses that do not trigger a manifestation of the disease under normal conditions. ADSCs harvested from a dog`s omentum with canine distemper disease were found to be infected with canine morbillivirus [103]. In this study, before the clinical use of ADSCs, cells were checked for the presence of latent viruses.

Currently, the major dilemma with fat grafting, as well as with other biological grafts and substances, is inconsistent results of experimental and clinical findings attributable to poor standardization resulting from wide varieties of harvesting methods, donor sites, and patients’ initial state of health, as well as a lack of established, objective methods for assessment of clinical results and a lack of knowledge on the precise mechanism of stem cell action and regenerative mechanisms. There is also a lack of data and evidence from which to draw conclusions regarding the safety, effectiveness, and impact of ADSCs and other adipose tissue grafts on tissue regeneration [104].

The main issues that should undergo standardization are adipose tissue harvesting and processing, donor`s health condition, age, cryopreservation and storage procedure, freezing media that was used, quantification of ADSCs number and their phenotypical markers, storage duration, dosage used for the treatment of particular disease etc. Moreover, apart from three main widely accepted criteria for ADSCs – such as plastic-adherent during culturing, trilineage mesenchymal differentiation and expression of specific cell-surface antigens – a functional analysis of ADSCs properties (doubling time, specter and quantity of cytokines secretion, migration speed etc.) should be checked and compared to some standard in order to receive a predictable treatment result.

2.7 Latest clinical studies implementing ADSCs

The number of clinical trials using MSCs has recently significantly increased owing to notable successes and breakthroughs in basic research and experimental studies. New properties and clinical actions of MSCs have been discovered, and their clinical applications and indications have broadened.

Clinical studies have shown that infusion of MSCs leads to vigorous anti-inflammatory effects characterized by lymphocytosis and a decrease in levels of overactivated pro-inflammatory immune cells and TNF-α, in contrast to upregulation of IL-10 secretion. MSCs are known to auto-induce and address their microenvironment to promote cell proliferation and tissue regeneration. MSCs act via paracrine effects on cells and the organ environment, reducing cytokine storms and severe inflammation [105]. MSCs have been shown to demonstrate antimicrobial properties, increasing the immune response through the production of bactericide peptides and proteins, and the expression of indoleamine 2,3-dioxygenase (enzyme that decrease reproduction rate of viruses, some mammalian cells) and IL-17 [106]. ADSCs have proven efficient in the treatment of pulmonary diseases in vivo targeting a paracrine pathway, through the promotion of the epitheliocytes mitosis and apoptosis suppression [107]. The outcomes and limitations of clinical and randomized clinical trials with adipose tissue grafting products are shown in Table 2.

Table 2 Outcomes and limitations of using adipose-derived stem cells, based on clinical trials
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3 Conclusion

The last five years have witnessed a huge breakthrough in the translation of basic research and experimental studies of ADSCs into clinical practice. ADSCs are the most promising and easy-to-obtain cells when compared to other MSCs because of their satisfactory cultural, biological, and clinical properties. The future of ADSC-based therapies likely belongs to allogeneic ADSCs. ADSC-based treatment is a highly promising method that utilizes etiological treatment approaches for diseases that are accompanied by cell death or acute tissue loss such as diabetes mellitus type I, xerostomia, periodontitis, and wound treatment for them stem cell therapy. ADSCs act through their differentiation to the specific type of mature cells which are determined by the particular microenvironment or cell stimuli or via paracrine regulation, such as secretion of growth factors and cytokines.

The clinical translation of ADSCs requires proper validation in large controlled trials, discovery of the exact mechanism of action, research standardization, and the adoption of pre-determined therapeutic guidelines.

The vast majority of pre-clinical in vivo studies showed positive treatment outcomes, however there were only a few clinical trials performed, indicating that enough clinical evidence is not yet available to allow broad ADSCs implementation into clinical practice. Among the limiting factors are: small patient sample sizes, predominantly short-term observation time, a lack of adipose tissue graft standardization (procedure and cite of the graft harvesting, cell culturing protocols), deficit of clinical protocols and guidelines, and subjective scoring methods for clinical study results (such as visual assessment and patients’ response to pain) [22]. Currently, most preclinical studies and clinical trials reported that ADSCs are relatively safe and effective [104, 115]. The issue of dose, quality of the graft and indications remains unresolved and debatable [62]. According to the reviewed literature analysis, adipose tissue-derived biological products such as (ADSCs, SFV, ADSCs-Ev) showed promising results in clinical and in vivo setting. However, one of the main limitations of ADSCs therapy, as all other biologics-based drugs, is a process of the graft standardization. Such standardization should take into consideration the functional properties of the graft, such as doubling time, specter and quantity of cytokines secretion, migration speed etc., all of which varied based on the procedure of their isolation, localization, and pretreatment used in order to provide predictable and effective treatment outcomes.