TY - JOUR
T1 - Bone formation by human paediatric marrow stromal cells in a functional allogeneic immune system
AU - Palomares Cabeza, Virginia
AU - Fahy, Niamh
AU - Kiernan, Caoimhe H.
AU - Lolli, Andrea
AU - Witte-Bouma, Janneke
AU - Fahmy Garcia, Shorouk
AU - Merino, Ana
AU - Kops, Nicole
AU - Ridwan, Yanto
AU - Wolvius, Eppo B.
AU - Brama, Pieter A.J.
AU - Hoogduijn, Martin J.
AU - Farrell, Eric
N1 - Publisher Copyright:
© 2024 The Author(s)
PY - 2024/4
Y1 - 2024/4
N2 - Allogeneic stem-cell based regenerative medicine is a promising approach for bone defect repair. The use of chondrogenically differentiated human marrow stromal cells (MSCs) has been shown to lead to bone formation by endochondral ossification in immunodeficient pre-clinical models. However, an insight into the interactions between the allogeneic immune system and the human MSC-derived bone grafts has not been fully achieved yet. The choice of a potent source of MSCs isolated from pediatric donors with consistent differentiation and high proliferation abilities, as well as low immunogenicity, could increase the chance of success for bone allografts. In this study, we employed an immunodeficient animal model humanised with allogeneic immune cells to study the immune responses towards chondrogenically differentiated human pediatric MSCs (ch-pMSCs). We show that ch-differentiated pMSCs remained non-immunogenic to allogeneic CD4 and CD8 T cells in an in vitro co-culture model. After subcutaneous implantation in mice, ch-pMSC-derived grafts were able to initiate bone mineralisation in the presence of an allogeneic immune system for 3 weeks without the onset of immune responses. Re-exposing the splenocytes of the humanised animals to pMSCs did not trigger further T cell proliferation, suggesting an absence of secondary immune responses. Moreover, ch-pMSCs generated mature bone after 8 weeks of implantation that persisted for up to 6 more weeks in the presence of an allogeneic immune system. These data collectively show that human allogeneic chondrogenically differentiated pediatric MSCs might be a safe and potent option for bone defect repair in the tissue engineering and regenerative medicine setting.
AB - Allogeneic stem-cell based regenerative medicine is a promising approach for bone defect repair. The use of chondrogenically differentiated human marrow stromal cells (MSCs) has been shown to lead to bone formation by endochondral ossification in immunodeficient pre-clinical models. However, an insight into the interactions between the allogeneic immune system and the human MSC-derived bone grafts has not been fully achieved yet. The choice of a potent source of MSCs isolated from pediatric donors with consistent differentiation and high proliferation abilities, as well as low immunogenicity, could increase the chance of success for bone allografts. In this study, we employed an immunodeficient animal model humanised with allogeneic immune cells to study the immune responses towards chondrogenically differentiated human pediatric MSCs (ch-pMSCs). We show that ch-differentiated pMSCs remained non-immunogenic to allogeneic CD4 and CD8 T cells in an in vitro co-culture model. After subcutaneous implantation in mice, ch-pMSC-derived grafts were able to initiate bone mineralisation in the presence of an allogeneic immune system for 3 weeks without the onset of immune responses. Re-exposing the splenocytes of the humanised animals to pMSCs did not trigger further T cell proliferation, suggesting an absence of secondary immune responses. Moreover, ch-pMSCs generated mature bone after 8 weeks of implantation that persisted for up to 6 more weeks in the presence of an allogeneic immune system. These data collectively show that human allogeneic chondrogenically differentiated pediatric MSCs might be a safe and potent option for bone defect repair in the tissue engineering and regenerative medicine setting.
KW - Allogeneic
KW - Bone
KW - Endochondral ossification
KW - Mesenchymal stem cell/marrow stromal cell
KW - Tissue Engineering
UR - http://www.scopus.com/inward/record.url?scp=85185395029&partnerID=8YFLogxK
U2 - 10.1016/j.biomaterials.2024.122471
DO - 10.1016/j.biomaterials.2024.122471
M3 - Article
AN - SCOPUS:85185395029
SN - 0142-9612
VL - 306
JO - Biomaterials
JF - Biomaterials
M1 - 122471
ER -