Suppression of the immune system as a critical step for bone formation from allogeneic osteoprogenitors implanted in rats

Abstract

The surface marker profile of mesenchymal stromal cells (MSCs) suggests that they can escape detection by the immune system of an allogeneic host. This could be an optimal strategy for bone regeneration applications, where off-the-shelf cells could be implanted to heal bone defects. However, it is unknown how pre-differentiation of MSCs to an osteogenic lineage, a means of improving bone formation, affects their immunogenicity. Using immunohistological techniques in a rat ectopic implantation model, we demonstrate that allogeneic osteoprogenitors mount a T cell- and B cell-mediated immune response resulting in an absence of in vivo bone formation. Suppression of the host immune response with daily administration of an immunosuppressant, FK506, is effective in preventing the immune attack on the allogeneic osteoprogenitors. In the immunosuppressed environment, the allogeneic osteoprogenitors are capable of generating bone in amounts similar to those of syngeneic cells. However, using osteoprogenitors from one of the allogeneic donors led to newly deposited bone that was attacked by the host immune system, despite the continued administration of the immunosuppressant. This suggests that, although using an immunosuppressant can potentially suppress the immune attack on the allogeneic cells, optimizing the dose of the immunosuppressant may be crucial to ensure bone formation within the allogeneic environment. Overall, allografts comprising osteoprogenitors derived from allogeneic MSCs have the potential to be used in bone regeneration applications.

Local induction of inflammation affects bone formation

“…However, at the time of explantation, we found a negative correlation between the presence of lymphoid cell clusters and the amount of bone tissue formation caused by BMP-2. In agreement with others (Chatterjea et al, 2014), we show that these cell infiltrations are likely a mixed population of B and T cells. Interestingly, LTA-loaded constructs presented the lowest number of lymphoid cells, while the opposite association was seen for LPS-loaded constructs.…”

“…Alternatively, their activation could also occur secondarily to the innate immune response (MacLeod et al, 2007;Zanin-Zhorov et al, 2007). The local presence of adaptive immune cells can be both stimulatory (Nam et al, 2012;Ono et al, 2016) or inhibitory (Chatterjea et al, 2014;Liu et al, 2011;Reinke et al, 2013) for bone regeneration, and is likely dependent on the contribution of specific T cell subsets.…”

Changes in immunological profile of allogeneic mesenchymal stem cells after differentiation: should we be concerned?

“…Similarly, Liu and colleagues [ 7 ] and Arinzeh and colleagues [ 32 ] implanted ex vivo osteogenically differentiated cells in vivo in a leporine and canine model, respectively, and found that these cells incorporated into the host tissue, functioned as osteoblasts and resided in situ for at least 28 days without overt signs of rejection such as hypercellularity. In contrast to these data, however, it has been reported by others that implanted allogeneic MSCs require immunosuppressive treatment to survive and differentiate in vivo, and are rapidly cleared by infiltrating immune cells in the absence of such immunosuppression [ 34 , 35 ]. Additionally, expression of immunogenic molecules such as Swine leukocyte antigen-I (SLA-I) on differentiating allogeneic porcine MSCs was shown to reduce the in vivo efficacy of the treatment when compared to allogeneic MSCs that had SLA-I knocked down [ 36 ].…”

Stem Cell Considerations for the Clinician

“…However, recently other studies have shown MHC II expression presents following stimulation with interferon gamma (41), after chondrogenic differentiation (42) (43) (44) or osteogenic differentiation (45). Others have found that immunosuppressive therapy is needed for differentiated MSC to survive and evade infiltrating immune cells (46, 47). This has raised concern for the longevity of allogeneic cells in the donor recipient (48) particularly for therapies where the differentiated cell type is important such as cartilage replacement in OA.…”