Abstract
Dear Editor,
We read with great interest the recent article entitled “Regional implantation of autologous adipose tissue-derived cells induces a prompt healing of long-lasting indolent digital ulcers in patients with systemic sclerosis” by Del Papa et al. (6). In the article, authors provided very demonstrative data supporting the efficiency of adipose tissue-derived cells in reducing digital ulcers unresponsive to conventional therapies in 15 patients with systemic sclerosis (SSc). Such results add to recently published clinical trials (1,7) extending the therapeutic use of autologous fat tissue to the field of SSc-related vascular/ischemic complications.
In the article, the authors used for the first time the term “adipose tissue-derived cells (ATDCs) fraction” and mentioned that it contains both adipose stem cells (ASCs) and stromal vascular components. This terminology may be misleading and hamper a proper understanding of the underlying mechanisms involved in the therapeutic effect of the adipose tissue-derived cell products.
Since the description by Zuk and colleagues of a population of multipotent cells within the stromal vascular fraction (SVF) of adipose tissue (10), thousands of articles have been published, and various terminologies have been used to define these cells: adipose-derived stem cells (ADSCs), adipose-derived adult stem cells (ADAS), adipose-derived mesenchymal stem cells (AD-MSCs), adipose mesenchymal stem cells (AMSCs), and adipose stromal/stem cells (ASCs) (9). Recently, the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT) published a joint statement to provide initial guidance for the scientific community working with adipose-derived cell products and facilitate the development of international standard-based studies (2). In this statement, the term “stromal vascular fraction” refers to a set of cells obtained after enzymatic digestion of adipose tissue and separated from mature adipocytes using differential centrifugation. Thus, SVF is a heterogeneous population of cells containing hematopoietic cells, pericytes, endothelial cells and progenitors, and stromal/stem cells. By contrast, the term “adipose-derived stromal/stem cells (ASCs)” is used to name the plastic-adherent, ex vivo cultured, and serially passaged, multipotent cell population isolated from SVF. These cells display multilineage differential potential (adipogenic, osteogenic, and chondrogenic) and are minimally characterized by the expression of CD13, CD73, and CD90 and the lack of CD45 and CD11b hematopoietic markers.
In the article by Del Papa et al., ATDCs were obtained after a centrifugation (3 min at 920 × g) of the lipoaspirate and removal of “the upper and lower phases, containing oil supernatant and mature adipocytes, and blood and plasma residuals, respectively.” As neither cell culture nor enzymatic digestion was performed, this process may not allow the specific isolation of ASCs or SVF, but rather correspond to the Coleman fat grafting procedure (3,4). In this technique, fat tissue purified by centrifugation of lipoaspirates is used as a soft tissue filler and can be transferred in small aliquots into several layers of host sites.
Several histological studies have suggested that native ASCs are rarely distributed among adipocytes and reside in a vascular niche associated to adipose microvasculature where they coexist with pericytes and endothelial (progenitor) cells (5,8). Therefore, the dramatic result on DU healing observed after regional implantation of ATCDs in patients with SSc raises the following questions: i) Does the presence of adipocytes in the fat autografts predominantly contribute to the stimulation of ulcer healing? ii) Does transfer of the ADTCs fraction associated to unprocessed adipose tissue create an optimal environment that protects the perivascular niche and supports the regenerative effect of cells and growth factors within ischemic host tissues? iii) Could the local effect of small amounts of injected ATDCs last more than isolated regenerative and immune cells from the SVF?
One other major pitfall in the therapy of SSc fingers is the potential increase of intratissue pressure related to the injection of fat tissue in a permanent ischemic context. We noticed that the authors performed a small skin incision in the site of injection to reduce the intratissue pressure due to the introduction of the additional material with an 18-gauge cannula. We wonder if local healing was rapidly obtained as the authors did not mention these data.
To circumvent this safety issue, the therapeutic option chosen by Granel and colleagues (7) was to use the SVF, taking advantage of its liquid consistency, for treatment of SSc hand disability. Under neurolept analgesia, entry points were performed using a 25-gauge needle on the edges of each finger, at the junction of palmar and dorsal faces, at the level of the metacarpophalangeal joint for the thumb, and the proximal interphalangeal joint for long fingers. SVF was then injected using a 25-gauge reinforced blunt cannula placed into the subcutaneous tissue in contact with the neurovascular pedicles: 0.5 ml of the solution was injected into each lateral side of each digit, using a retro-tracing technique, from distal to proximal. Results showed a statistically significant improvement of hand disability measured with numerous parameters. Although the primary objective of the study was not the healing of DUs, a reduction in DU number (from 15 to 7) and size (from 3.3 ± 2.4 mm to 1.4 ± 0.8 mm diameter) was observed at 6 months in 12 SSc patients.
In conclusion, fat autograft and SVF injection are emerging as promising strategies for DU healing as well as hand disability in SSc patients. Future controlled and comparative studies are now expected to establish safety and efficacy. Respect of the correct IFATS and ISCT nomenclature in scientific publications is strongly recommended. In addition, a better knowledge of the different mechanisms underlying the clinical efficacy is still required for an optimal development of these cell-based therapies.