###### Abstract  
Low back pain (LBP) is one of the most frequent symptoms associated with intervertebral disc degeneration (IDD) and affects more than 80% of the population, with strong psychosocial and economic impacts. The main cause of IDD is a reduction in the proteoglycan content within the nucleus pulposus (NP), eventually leading to the loss of disc hydration, microarchitecture, biochemical and mechanical properties. The use of mesenchymal stem cells (MSCs) has recently arisen as a promising therapy for IDD. According to numerous reports, MSCs mediate their regenerative and immunomodulatory effects mainly through paracrine mechanisms. Recent studies have suggested that extracellular vesicles (EVs) extracted from MSCs may be a promising alternative to cell therapy in regenerative medicine. EVs, including exosomes and microvesicles, are secreted by almost all cell types and have a fundamental role in intercellular communication. Early results have demonstrated the therapeutic potential of MSCs-derived EVs for the treatment of IDD through the promotion of tissue regeneration, cell proliferation, reduction in apoptosis and modulation of the inflammatory response. The aim of this review is to focus on the biological properties, function, and regulatory properties of different signaling pathways of MSCs-derived exosomes, highlighting their potential applicability as an alternative cell-free therapy for IDD. Keywords:extracellular vesicles; exosomes; mesenchymal stem cells; miRNA; low back pain; intervertebral disc degeneration; regenerative medicine +
Footnote †: journal:  
_Applied_  
_sciences_  
_Repiew_  
**Mechanymal Stem Cell-Derived Exosomes: The New Frontier for the Treatment of Intervertebral Disc Degeneration**  
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**V.T.T. extracellular matrix (ECM) rich in proteoglycans (mainly aggrecan), type II collagen and other proteins such as elastin and fibronectin. The high level of water content helps maintain disc height and supports the functions of the IVD [7]. The NP cell population has a notochordal origin: notochordal cells (NCs) act as progenitor cells and play an important role in stimulating ECM synthesis by NP cells (NPCs), although in adult human NP tissue the number of NCs diminishes drastically [8]. To preserve IVD architectural features, it is essential to maintain disc cell metabolism and physiological biomechanics, but the avascular and relatively acellular environment of the NP leads to a limited regenerative capacity against stressful and degenerative stimuli. IDD is an age-related disease and is mainly linked to loss of NP hydration and reduction in the proteoglycan content [9]. Current approaches to treat IDD are based on conservative or surgical procedures that aim to relieve the symptoms; however, they are not able to change the natural history of the disease [10]. Recent advances in the understanding of IVD biology have led to an increased interest in the development of novel biological treatments. Growth factors, gene therapy, stem cell transplantation and tissue engineering might support intervertebral disc regeneration [11; 12; 13; 14; 15; 16]. The transplantation of mesenchymal stem cells (MSCs), including bone marrow-derived (BM-MSCs) and adipose tissue (Ad-MSCs), has been evaluated in different clinical trials. Although encouraging results have been achieved, there are still several impediments related to the survival and differentiation of transplanted MSCs due to the particularly hostile microenvironment of degenerated IVDs [17]. Moreover, costs related to cell expansion under Good Manufacturing Practice (GMP) conditions and to the quality control guidelines for Advanced Therapy Medical Products (ATMP) limits the large-scale application of a cell therapy strategy.