Adipose-Derived Mesenchymal Stem Cells as the Panacea for Degenerative Joint Diseases: Fact or Fiction?

The continuously evolving society of the third millennium
requires more and more athletic skills for citizens of all countries.


Introduction
The continuously evolving society of the third millennium requires more and more athletic skills for citizens of all countries.
Given the increasing life expectancy, together with the global trend to obesity and the increasing number of sport-related injuries at all ages, degenerative joint pathologies are becoming an enormous medical and socio-economic burden [1]. Non-surgical treatments, such as physio kinesitherapy, pharmacological treatments, hyaluronic acid (HA) or its derivatives, temporarily target the symptoms but cannot prevent the degenerative process [2]. Jointpreserving surgical treatments, such as arthroscopic shaving, provide temporary relief of symptoms [3]. In this context, the biological approaches have recently gained more attention among orthopedics clinicians and surgeons, and in particular mesenchymal stem cells (MSCs), for their ability to act not only on cartilage, but on the whole joint environment [4]. Initially, MSCs were described by Caplan [5] as pluripotent cells, easily isolated from different tissues (including bone marrow, adipose tissue, synovial capsule), which can differentiate into different cell lineages (such as bone, cartilage, muscle, and tendons), contributing in this way to repair the damaged area.
More recently, several clinicians emphasized their paracrine effect to secret various cytokines and growth factors (GF) to adjacent cells, leading to vascularization and cellular proliferation in damaged tissues, and their immunomodulatory properties, so they can reduce inflammation in injured tissues [4]. The definition of Medicinal Signaling Cells, proposed by the same Caplan, represents a more comprehensive attempt to describe the potential of this issue, however not yet fully clarified [6]. Adipose-derived mesenchymal stem cells (AMSCs), firstly identified in the early 2000s [7], offer some intrinsic advantages that deserves particular attention; AMSCs are easily harvested from subcutaneous tissue in large quantities, with low morbidity of the patients, and can easily be isolated and expanded in vitro [8][9][10][11]. Moreover, AMSCs have been shown to be immunoprivileged, with low risk of rejection, and more genetically stable in long term culture, with a greater proliferative rate than MSCs isolated from other tissues, in particular bone marrow [12][13][14][15].
In addition, AMSCs induce a trophic effect through the secretion of a large number of GF and anti-inflammatory proteins in response to inflammatory molecules, including prostaglandin 2, hepatocyte growth factor, transforming growth factor-β1, vascular endothelial growth factor, tumor necrosis factor-α , stromal cellderived factor-1, nitrous oxide, IL (interleukin)-4, IL-6, IL-10, and IL-1 receptor antagonist, that support the angiogenesis, tissue remodeling, and antiapoptotic events [16][17][18]. However, the real potential of these cells remains unknown, since culture expanded AMSC are usually considered to be a pharmaceutical product requiring government regulatory clearance; due to such government regulatory issues, stromal vascular fraction (SVF) has been more commonly used for various orthopedic applications

Clinical Results
In Literature, more than 5,000 articles dealing with the potentialities of ADSC are currently available, but, in our acknowledgement, only 23 papers     [48,49]. Moreover, currently, evidence of malignant transformation of MSCs is lacking [48]. It should, however, be noted that the follow-up time in these analyses was yet limited and a chance of considerable risk is still possible.
Nonetheless, long-term adverse events are still poorly researched.

Conclusion
In conclusion, it is impossible with actual knowledge to identify the real potential of this fascinating possibility of therapy.
Numerous studies are currently in progress to clarify questions that still remain unanswered, regarding the long-term durability of these procedures, the possible modifications that have to be done to achieve better results, and the best-performing biological agents for each given kind of patient and/or grade of disease. In the meanwhile, more high-quality studies should be performed to validate their safety, first, and then efficacy.