Chondrogenic Differentiation Increases Antidonor Immune Response to Allogeneic Mesenchymal Stem Cell Transplantation

Abstract

Allogeneic mesenchymal stem cells (allo-MSCs) have potent regenerative and immunosuppressive potential and are being investigated as a therapy for osteoarthritis; however, little is known about the immunological changes that occur in allo-MSCs after ex vivo induced or in vivo differentiation. Three-dimensional chondrogenic differentiation was induced in an alginate matrix, which served to immobilize and potentially protect MSCs at the site of implantation. We show that allogeneic differentiated MSCs lost the ability to inhibit T-cell proliferation in vitro, in association with reduced nitric oxide and prostaglandin E2 secretion. Differentiation altered immunogenicity as evidenced by induced proliferation of allogeneic T cells and increased susceptibility to cytotoxic lysis by allo-specific T cells. Undifferentiated or differentiated allo-MSCs were implanted subcutaneously, with and without alginate encapsulation. Increased CD3(+) and CD68(+) infiltration was evident in differentiated and splenocyte encapsulated implants only. Without encapsulation, increased local memory T-cell responses were detectable in recipients of undifferentiated and differentiated MSCs; however, only differentiated MSCs induced systemic memory T-cell responses. In recipients of encapsulated allogeneic cells, only differentiated allo-MSCs induced memory T-cell responses locally and systemically. Systemic alloimmune responses to differentiated MSCs indicate immunogenicity regardless of alginate encapsulation and may require immunosuppressive therapy for therapeutic use.

Avoidance of total knee arthroplasty in early osteoarthritis of the knee with intra-articular implantation of autologous activated peripheral blood stem cells versus hyaluronic acid: A randomized controlled trial with differential effects of growth factor addition

“…HSCs have also been hypothesized to be the source of all cells in our body which makes PBSC the ideal cellular source both in terms of easiness of collection, cell numbers, safety, and efficacy [65]. The downsides of MSC expansion with cytogenetic instability and risk of malignant transformation are thus avoided [31] as well as the ever-present risk of immune rejection when allogeneic MSCs (especially when chondrogenic differentiation is induced) are injected [27]. Allogeneic, cultured, and expanded stem cells may present wider and more challenging issues than the well-known onerous immunological tissue antigen MHC incompatibility [27].…”

“…The downsides of MSC expansion with cytogenetic instability and risk of malignant transformation are thus avoided [31] as well as the ever-present risk of immune rejection when allogeneic MSCs (especially when chondrogenic differentiation is induced) are injected [27]. Allogeneic, cultured, and expanded stem cells may present wider and more challenging issues than the well-known onerous immunological tissue antigen MHC incompatibility [27]. Epigenetic dysynchronicity with incongruent gene methylation status and thus discordant gene products, divergent secretomes, and micro-RNA products as well as differences in nutrient sensing between donor and recipient tissues are issues that are only recently being researched and may present even bigger regenerative hurdles [66].…”

“…Safety was the paramount in our choice. In nonhematological regenerative uses, we believe that an autologous origin of stem cells must be the only choice as the use of allogeneic sources is invariably tainted with an inherent risk of rejection and unease for potentially life-threatening complications [26,27], the need for future immunosuppression [27], and the concern for a diminished effect due to immunovigilance [26][27][28] as well as worsening of inflammation in OA [27] or malignancies [29]. Moreover, allogeneic sources are usually preferred for obvious commercial and patentrelated reasons and not due to ease of procurement or cost [30].…”

Structured ultrasound microscopy

“…Undifferentiated BMSCs have been shown to inhibit the differentiation, maturation, and function of DCs (Jiang et al, 2005;Spaggiari, Abdelrazik, Becchetti, & Moretta, 2009;Zhang et al, 2004), however, little is known about the effect of chondrogenically differentiated BMSCs on DCs. Chondrogenically differentiated BMSCs have been reported to be more immunogenic compared with undifferentiated BMSCs (Chen et al, 2007;Ryan et al, 2014). However, few studies have directly cocultured chondrogenically differentiated BMSC pellets and immune cells.…”

“…Rosendahl, Zetterberg, & Ringden, 2003;Lohan et al, 2014;Ryan et al, 2014;Sudres et al, 2006). It is unclear whether these immunomodulatory properties are maintained upon differentiation.…”