Mesenchymal stem cells for the treatment of psoriasis: a comprehensive review

Mesenchymal stem cells (MSCs) have recently been shown to have not only regenerative capabilities but also immunomodulating properties. For this reason, they are currently under investigation in clinical trials for the treatment of several autoimmune systemic disorders. Psoriasis is a systemic immune‐mediated disease for which MSCs could have therapeutic potential. We analysed the existing literature with regard to MSC‐based strategies for the treatment of psoriasis, using the MEDLINE, Embase, Scopus and Cochrane Library electronic databases from inception to the date of study. A number of studies confirm the involvement of MSCs in psoriasis pathogenesis and therefore designate MSCs as an important potential therapeutic tool in this setting. Preclinical data are mostly based on imiquimod‐induced murine models of psoriasis, and confirm the anti‐inflammatory and immunomodulatory action of MSCs in the setting of psoriasis. Six patients affected by psoriasis were described in four clinical studies. Despite significant differences in terms of therapeutic protocols and clinical outcomes, the MSC‐based regimens were efficacious in 100% of the cases. Despite more data still being needed, MSCs could be a promising therapy for psoriasis.


Introduction
Psoriasis is a chronic, relapsing inflammatory disease affecting 2-3% of the population, and is considered to be a systemic disease rather than one limited to the skin. 1 The treatment varies, depending on disease severity, from topical agents and phototherapy to conventional immunosuppressant drugs and biologic agents. 2 The pathogenesis of psoriasis has an immunological basis. A central role is certainly played by T helper (Th)1 and Th17 lymphocytes and by cytokines such as tumour necrosis factor (TNF)-a, interleukin (IL)-17 and IL-23. 3 However, recent studies have shown that the prime mover in psoriasis pathogenesis could be linked to a dysfunction in resident mesenchymal stem cells (MSCs), resulting in altered polarization of the immune response. 4 most widely studied being the bone-marrow stromal stem cells (BMSCs). Other MSCs are, for example, amniotic fluid stem cells, umbilical-cord MSCs (UCMSCs) and adipose-derived stem cells (ADSCs); these last are contained in the stromal-vascular fraction (SVF) of adipose tissue. 6 MSCs are under study not only for their regenerative capacity, but also for their immunomodulating properties, as they seem to be able to directly modulate cytokine secretion from lymphocytes. 7 A recent work demonstrated that skin MSCs from patients with psoriasis have low differentiation capacity, high human leucocyte antigen-I expression levels and low immunoregulatory capability. 8 Lymphocyte inhibition seems to be compromised in psoriatic skin, mainly because of dermal MSCs, leading to abnormalities in cytokine secretion through circular RNA. 9,10 Moreover, MSCs from psoriatic plaques have been shown to promote keratinocyte proliferation, with subsequent abnormal thickening of the epidermis. 11 Several papers have also reported that MSCs seem to be key players in mediating the pleiotropic effects of biologic therapies on both keratinocytes and T cells. 12 Campanati et al. demonstrated that the effects of TNFa inhibitors take place at the level of dermal MSCs, which probably represent the cells primarily involved in the 'psoriatic march'. 13,14 In this setting, several authors are investigating the role of MSCs as a possible therapeutic strategy for the treatment of psoriasis (Table 1).

Preclinical models
Preclinical data are mostly based on imiquimod (IMQ)induced murine models of psoriasis. MSCs demonstrate efficacy in reduction of disease severity, acanthosis, inflammatory infiltrate and cytokine production. 19,20 In particular, two studies showed the curative potential of subcutaneous injection of UCMSCs, which seem to act through direct action both on T lymphocytes Figure 1 Schematic representation of mesenchymal stem cells (MSCs). MSCs are a subset of pluripotent cells present in tissues of mesenchymal origin, such as bone marrow, adipose tissue, placenta, umbilical cord, dermis, skeletal muscle, lungs (upper panel). MSCs are characterized by the presence of specific surface markers such as CD105, CD73 and CD90 (green box). However, MSCs by definition lack CD45, CD34, CD14, CD19 and HLAII molecules (red box). Their pluripotency and their regenerative properties are demonstrated by their ability to differentiate into adipocytes (yellow), chondrocytes (pink) and osteocytes (red) in vitro (lower left panel). MSCs also interact with both lymphocytes and dendritic cells, therefore modulating cytokine secretion. Created with BioRender.com and dendritic cells (DCs), and the study stressed the importance of an antioxidative milieu for the correct action of MSCs. 15,16 Those data were recently confirmed by Chen et al., who demonstrated UCMSC-induced reduction in the production of type I interferon by plasmacytoid DCs. 17 Only one preclinical study has been performed on ADSCs, which showed that IMQ-induced inflammatory changes are inhibited after intradermal injection of ADSC. 18 Human tonsil-derived MSCs were able to prevent Th17-mediated autoimmune response via regulation of the programmed death-1/programmed death ligand-1 pathway. 21 Moreover, Campanati et al. recently confirmed the in vitro capability of dermal MSCs taken from healthy controls to revert the proinflammatory cytokine production by aberrant MSCs obtained from psoriatic plaques (p-MSCs) and to lower p-MSC proliferation rates when in coculture. 22 Clinical case reports Our review identified four clinical studies describing a total of six patients affected by psoriasis treated with MSC-based regimens ( Table 2). The patients generally had a long-standing history of psoriasis (mean 14.8 years) and most of them were previously prescribed both topical and systemic treatments. All patients were weaned off any systemic medication for psoriasis before any MSC-based treatment was administered. Unlike in haematopoietic-stem-cell transplant (HSCT), no concomitant drugs are needed before MSC administration.
In a report from Chen et al., 23 heterologous UCMSCs were infused intravenously in two patients with psoriasis. One patient also underwent HSCT for underlying cancer and not primarily because of psoriasis, therefore making it difficult to draw conclusions on MSC effectiveness in that particular case. 23 De Jesus et al. 24 described two patients with psoriasis who were infused with autologous ADSCs, which had been obtained through centrifugation and enzymatic digestion of lipoaspirates and subsequent plating. While one patient received two doses of ADSCs, the other required three doses. Both patients experienced significant cutaneous improvement of but did not reach complete clearance, and therefore required additional therapies. One of the patients also had psoriatic arthritis, which did not respond to the ADSCbased treatment.
Comella et al. 25 recently published a report on successful intravenous injection of autologous SVF in a patient affected by psoriasis. Fresh SVF from lipoaspirate was resuspended in normal saline solution for administration through a 23G butterfly needle. The patient experienced complete clearance of the disease, with no recurrences during the followup period.
Seetharaman et al. 26 also described the efficacy of topical application of ADSC-conditioned medium (CM) in a localized form of scalp psoriasis. ADSCs from a healthy volunteer were plated and the MSC-CM was collected after 72 h of incubation, centrifuged, filtered, concentrated by ultrafiltration and stored at À20°C until use. MSC-CM was applied directly to the affected   area on a daily basis for 30 days, with significant clinical improvement and stable results. In all four studies, the efficacy of the MSC-based regimen was 100%. Only two of the six patients relapsed, but the relapses after MSC-based treatment regimens were generally milder forms of psoriasis and responded to systemic therapy. No serious adverse events were registered. TBC reactivation and infections were seen only in patients receiving concomitant immunosuppression or biologic therapies.

Discussion
MSCs are currently used in clinical trials for a great variety of diseases, with a special focus on autoimmune disorders. 27 The feasibility of MSC transplantation is highly dependent on the type of cell used: for example, while BMSC isolation requires a specialist team, ADSCs are easily accessible and therefore a much simpler treatment.
Previous studies have already confirmed the involvement of MSCs in the pathogenesis of psoriasis and therefore designated MSCs as important potential therapeutic targets. 28 It is unclear if genetic polymorphisms responsible for genetic predisposition to psoriasis could represent a primary cause of MSC dysfunction. It remains undetermined whether the local dysfunction of MSC in psoriatic plaques is only a localized phenomenon or if it reflects a failure in MSC functioning in general. Moreover, the published studies display wide variation in terms of types of cell used and the methods of administration, therefore making it impossible at present to define a standardized protocol. Those are central points for future studies aimed at determining the feasibility and efficacy of autologous MSC transplantation.
Despite many promising reasons for the use of MSCs in psoriasis, it should also be noted that the direct regenerative potential of these cells may not be as effective as previously expected. There are also potential risks associated with MSC therapy, including graftversus-host disease, neoplastic proliferation, localized cutaneous reactions and lack of efficacy. The likelihood of those adverse events varies according to the type of cell used and the method of administration. Assessment of the potential risks and benefits is essential before MSC-based therapeutic regimens can be considered a treatment of choice for psoriasis. 29,30 Conclusion We analysed four studies on six patients that used MSC therapy for psoriasis. Although all six patients benefited from the treatment, there were relapses. MSC treatment is also not without risk. Further data are needed to determine whether MSC-based strategies could be included in official guidelines for the treatment of psoriasis.

Learning points
• MSCs do not only display regenerative capabilities but also have immunomodulating properties. • Th1 and Th17 lymphocyte inhibition is compromised in psoriatic skin, mainly because of MSCs in psoriatic lesions affecting the skin microenvironment.
• A central role is played by MSCs in the response to biologic therapies; MSCs in fact seem to be key players in mediating the pleiotropic effects of those drugs on both keratinocytes and T cells.
• Preclinical data were mostly based on IMQ-induced murine models of psoriasis, and confirmed the anti-inflammatory and immunomodulatory action of MSCs in the setting of psoriasis. • Several studies have demonstrated the efficacy of MSC administration both in patients with psoriasis and in animal models of psoriasis. • To date, only six patients affected by psoriasis have successfully been treated with MSC-based regimens • In addition, the wide variation in terms of types of cell and methods of administration mean that there are no standardized protocols.