Adipose-derived stem cells (ASCs) represents a promising tool not only for soft tissue engineering, but also for the treatment of severe pathologies, such as chronic intestinal inflammation, cardiovascular diseases and lung injury. Human ASC therapeutic efficacy is likely due to self-renewal properties, multilineage differentiation potential and immunomodulatory activity. Notwithstanding the use of ASCs in different clinical trials, the molecular mechanisms at the basis of their administration have to be fully elucidated. In particular, there is an urgent need to identify novel strategies aimed to a lifelong persistence of ASC properties for potentiating their therapeutic applications.
Non-coding RNAs (ncRNAs) and epigenetic changes, such as DNA methylation and histone modifications, have been suggested to have a role in the regulation of adult stem cell proliferation, vitality, differentiation potential and immunomodulatory capacities, since these molecular drivers can be finely tuned and reprogrammed. Importantly, many epi-molecules and ncRNAs can be secreted into micro-vesicles, the so-called secretome, which has recently emerged as a key factor in ASC-mediated paracrine effects, but the specific role in the different cellular processes has not yet been clarified.
In order to promote clinical applications of autologous ASCs, we aim to perform in vitro studies to assess the use of different epi-drugs and ncRNA-based approaches to boost ASC therapeutic characteristics, mainly immunomodulation, and to concomitantly reduce senescence mechanisms, which represent an important limit in cell-based therapies. Big data interrogation by using bioinformatic tools will help to identify key molecules and/or regulative pathways responsible for ASC properties, and would promote the development of new targeted strategies able to increase ASC plasticity and stability, so enhancing their efficacy in regenerative medicine of human pathologies.
The plasticity of adipose-derived stem cells (ASCs), together with the easily accessible way to obtain them from healthy tissues, strongly suggests the utilization of these cells for clinical applications in both immunological/autoimmune diseases and soft tissue defects. A cell-based approach might be useful for the treatment of soft tissue defects, which are a complex challenge for the plastic surgeon, and potentially led to prolonged hospitalization with protracted individual and economic burden. ASCs represent a valuable treatment option for a wide range of inflammatory or autoimmune diseases, which therapeutic efficacy relies primarily on immunomodulatory activities mediate by paracrine effects. An increasing number of preclinical studies and clinical trials are being developed to assess ASCs safety and efficacy. However, although there are promising results and increasing knowledge in the in vivo applications of ASCs, unfortunately, several clinical trials have failed due to differences in experimental protocols, readout, animal models and variability in ASCs characteristics.
Indeed, autologous ASC use showed consistent variations in clinical outcome, since cell characteristics may vary depending upon the disease. The presence of cardiovascular risk factors, as well as microenvironmental factors and metabolic disorders, seem to reduce ASC pluripotency and self-renewal, and also imply a remarkable reduction in their immunosuppressive activities, so discouraging their use in the clinical setting. On the other hand, the use of allogeneic stem cells is dependent on surgical procedures for adipose tissue availability, thus limiting the occurrence of overall healthy donors. Moreover, allogeneic ASCs showed donor-to-donor heterogeneity according to biological factors as age, sex, body mass index, and a potential immunogenicity, that might determine their rejection after infusion, cannot be excluded, especially at higher passages. Therefore, the clinical translation of ASCs still requires a proper validation in large controlled trials. For a more successful outcome of ASC based therapies, thorough investigations with more standardized protocols are urgently required, as well as a better understand of ASC immunomodulatory network and the identification of key molecules and/or regulatory mechanisms responsible for ASC effects in chronic inflammatory diseases. The in-depth analysis of the potential strategies aimed to boost ASC-mediated immunomodulation will foster new targeted approaches for cell therapy applications in the field of immune diseases. Yet, such interventions need to be accurately considered, since any alteration of immune system sensitivity can be dangerous: weakening the capacity of recognize transformed cells or pathogens, or vice versa exacerbating immune response, could lead to adverse events. In this context, epigenetic regulation might be more safe than genetic modifications, since engineered cells persisting in the host could generate undesirable effects, such as potential tumorigenicity related to genetic instability. Finally, the deep investigation of the molecular mechanisms at the basis of ASC secretome effects, and the establishment of protocols aimed to specifically improve its clinically relevant characteristics, might encourage the advance in secretome-based therapies. This approach would allow to overcome limitations connected with ASC intrinsic biological variability (for autologous use) and immunogenic potential (for allogeneic use), and will also turn out useful to facilitate clinical application by soften the regulatory requirements for manufacturing and quality control currently needed to establish the safety and efficacy profile of cell-based therapies.