Mesenchymal Stromal Cells Based Therapy in Systemic Sclerosis: Rational and Challenges

Abstract

Systemic Sclerosis (SSc) is a rare chronic disease, related to autoimmune connective tissue diseases such as Systemic Lupus Erythematosus and Sjögren's Syndrome. Although its clinical heterogeneity, main features of the disease are: extensive tissue fibrosis with increase matrix deposition in skin and internal organ, microvascular alterations and activation of the immune system with autoantibodies against various cellular antigens. In the diffuse cutaneous scleroderma subtype, the disease is rapidly progressive with a poor prognosis, leading to failure of almost any internal organ, especially lung which is the leading cause of death. Primary trigger is unknown but may involve an immune process against mesenchymal cells in a genetically receptive host. Pathophysiology reveals a pivotal role of fibrosis and inflammation alterations implicating different cell subtypes, cytokines and growth factors, autoantibodies and reactive oxygen species. Despite improvement, the overall survival of SSc patients is still lower than that of other inflammatory diseases. Recommended drugs are agents capable of modulating fibrotic and inflammatory pathways. Cellular therapy has recently emerged as a credible option. Besides autologous hematopoietic stem cell transplantation which demonstrated remarkable improvement, mesenchymal stromal cells (MSCs) represent promising therapeutic candidates. Indeed, these cells possess anti-inflammatory, antiproliferative, antifibrotic, and immunomodulary properties especially by secreting a large panel of bioactive molecules, addressing the most important key points of the SSc. In addition, these cells are very sensitive to their environment and are able to modulate their activity according to the pathophysiological context in which they are located. Autologous or allogeneic MSCs from various sources have been tested in many trials in different auto-immune diseases such as multiple sclerosis, Crohn's disease or systemic lupus erythematosus. They are characterized by a broad availability and no or low acute toxicity. However, few randomized prospective clinical trials were published and their production under ATMP regulatory procedures is complex and time-consuming. Many aspects have still to be addressed to ascertain their potential as well as the potential of their derived products in the management of SSc, probably in association with other therapies.

Mesenchymal stem cells of Systemic Sclerosis patients, derived from different sources, show a profibrotic microRNA profiling

“…At present, one third of the clinical trials using engrafting MSCs are designed to evaluate their therapeutic role in autoimmune diseases (for the latest update, see ttp://www.clinicaltrials.gov). Considering the immunomodulatory, pro-angiogenic and antifibrotic capabilities of MSCs, their transplant may have a potential application in cell-based therapies for SSc and results obtained in preclinical models 3,6,14,19,20,23 , as well as the few cases reported in the SSc 34,35 seem very promising. However, many in vitro experiments showed some differences in the biologic functions of SSc-MSCs, deriving from different tissues 3,6,22,23 .…”

Mesenchymal Stem Cells in Systemic Sclerosis: Allogenic or Autologous Approaches for Therapeutic Use?

“…In SSc, the main functions of MSCs are proposed to be anti-inflammatory to counteract the dysregulation of the immune system, anti-fibrotic to down-regulate the excessive production of collagen associated to thickening of skin and internal organs but also pro-angiogenic to counteract the widespread vasculopathy. A number of reviews have discussed the interest of using MSCs for the treatment of SSc (19, 59, 60). In the next paragraph, we focused our attention on the mechanisms that have been deciphered specifically in preclinical models of SSc.…”

Immunopathogenesis of Juvenile Systemic Sclerosis

“…Interestingly, dendritic cells helped to maintain the survival of the remaining ADSCs in fibrotic skin, and stimulating with the dendritic cell-derived signal lymphotoxin can enhance the survival and therapeutic effectiveness of intradermally injected ADSCs in a murine skin fibrosis model. ADSCs or a related type of mesenchymal stromal cells (MSCs) given either locally or systemically are being tested in human SSc (45); if clinical trials show efficacy of these approaches, it may be helpful to investigate whether adding lymphotoxin beta receptor stimulation can enhance these approaches (Figure 1).…”