Is adipose-tissue (or its fraction) grafting really effective in the treatment of scleroderma hand?

Autologous fat grafting, also simply referred to as lipofilling, has recently gained significant attention because of its efficacy not only in restoring volume to soft tissue, but also in improving skin quality thanks to its regenerative effects. At present, therapeutic procedures using various cellular components obtained from adipose tissue represent a common approach for the treatment of a variety of sclerotic changes, like scars, due to burns or trauma, and localized scleroderma [1, 2]. It is also believed that this methodology is applicable for the treatment of some local lesions that characterize the course and the evolution of systemic sclerosis (SSc) [2].

In this issue, Daumas et al. [3] report the results of a controlled trial in which adipose-derived stromal vascular fraction (SVF), obtained after mechanical separation and enzymatic digestion of whole autologous fat obtained by liposuction, was injected into the fingers of a group of 20 patients with SSc. The control placebo group constituted 20 matched patients with SSc who were only treated by injection of Ringer’s lactate solution in the same sites. The primary endpoint of the study was to obtain a significant improvement of the hand function in the treated group in comparison with the placebo group, as evaluated by a validated questionnaire. The secondary endpoints were improvement of skin fibrosis (evaluated by hand modified Rodnan skin score), pain (assessed by visual analogue scale), ulcers evolution assessed by recording ulcer healing and the appearance of new ulcers, and severity of Raynaud's phenomenon (RP).

None of the considered endpoints (primary and secondary) significantly differed in the treated group with respect to the placebo group when assessed at 3 and 6 months after the procedures [3]. The results of this French study are similar to those obtained in a controlled study conducted in the USA on a much larger number of scleroderma patients [4].

These negative results are completely in contrast to those obtained in a previous open study performed by the same French group on a more limited number of patients with SSc, where an appreciable improvement of hand function, RP and capillaroscopic microvascular abnormalities were observed [5].

A number of hypotheses can be raised to explain why the results of these studies are completely negative. First of all, it has been demonstrated that the SVF is rich in multipotent cells [namely adipose-derived stromal and stem cells (ADSCs)] with a high proliferation rate and wide potential differentiation toward cells of the mesoderm (i.e. adipogenic, osteogenic and chondrogenic) and endoderm (endothelial) lineages. In vitro studies have shown that the differentiation toward specialized cell types is dependent on the presence of specific induction factors in the medium where these stem cells are cultured [6, 7]. Thus, it is possible that the pathologic tissue where the ADSCs contained in the SVF and used in the Daumas et al. study were transferred to, may compromise their regenerative capacity and also induce a predominant fibroblastic lineage differentiation. In this respect, this hypothesis is strongly supported by the recent in vitro demonstration which showed that ADSCs treated with TGF-β or sera from scleroderma patients acquire a myofibroblast-like phenotype [8].

It is also worth noting that the Daumas et al. study gave negative results in ulcer outcome, since there was no difference in the number of healed ulcers and the number of newly appeared ulcers in the SVF-treated and in the placebo groups. These results are completely different from those observed in our previously study in which patients with SSc suffering from ischaemic digital ulcers were treated by only centrifuged adipose tissue grafting at the base of the involved fingers [9]. This procedure proved to be statistically superior to the sham procedure—where saline solution was injected using a similar methodology—in inducing ulcer healing, improving pain and increasing the number of capillary counts in videocapillaroscopy [9]. The substantial difference in the results obtained regarding ulcer outcome in this study with respect to the Daumas et al. trial can be explained in different ways. The first study was only aimed at observing the effect of adipose tissue grafting on ischaemic ulcers, and the patients were selected according to the presence of this clinical sign. In the Daumas et al. study, patient enrolment was not based on the presence of ulcers; some patients also had friction ulcers in addition to ischaemic digital ulcers, and the number of patients with ulcers of both types was very small in both the SVF grafting and placebo groups. The grafting site was different (the lateral part of each finger with respect to the base of finger). Finally, the grafted material was not the same, since it consisted of SVF in one case, and it was simply centrifuged fat in the other case.

Although the mechanical separation and enzymatic digestion of SVF can hypothetically be superior to the use of adipose tissue grafting in warranting a more elevated concentration of multipotent cells, since adipocytes and other cells are eliminated by this preliminary procedure, there is not clear demonstration that purified SVF has additional regenerative power with respect to whole fat. One can speculate that whole fat may include cell elements, growth factors or other biological molecules that can better stimulate tissue regeneration, and particularly endothelial repair, mostly in an ischaemic environment. Hypoxic conditions may also modulate the secretome of ADSCs toward an angiogenic regenerative pathway [10].

At present, published studies on the potential of fat (or its fraction) grafting in improving specific clinical features in patients with SSc are few, conducted on a limited number of patients and with completely different approaches, and all present important methodological limitations to support any definitive conclusions.

A great effort should be made to design more large multicentre investigations to better understand whether these experimental procedures may have a role in future therapeutic options in patients with SSc.

Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.

Disclosure statement: The authors have declared no conflicts of interest.

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