TY - JOUR
T1 - Endochondral Bone Regeneration by Non-autologous Mesenchymal Stem Cells
AU - Longoni, Alessia
AU - Pennings, I
AU - Cuenca Lopera, Marta
AU - van Rijen, M H P
AU - Peperzak, Victor
AU - Rosenberg, A J W P
AU - Levato, Riccardo
AU - Gawlitta, Debby
N1 - Funding Information:
The antibody against collagen type II (II-II6B3), developed by T. F. Linsenmayer, was obtained from the DSHB developed under the auspices of the NICHD and maintained by the University of Iowa, Department of Biology, Iowa City, IA52242. Furthermore, the help of Imke Jansen, Irina Mancini, and Lizette Utomo was highly appreciated. Finally, the authors would like to thank Anja van der Sar and Nicky van Kronenburg for all the support during the animal experiment. Funding. This work was supported by the AO Foundation (Project No. S-16-130G).
Publisher Copyright:
© Copyright © 2020 Longoni, Pennings, Cuenca Lopera, van Rijen, Peperzak, Rosenberg, Levato and Gawlitta.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/7/9
Y1 - 2020/7/9
N2 - Mimicking endochondral bone formation is a promising strategy for bone regeneration. To become a successful therapy, the cell source is a crucial translational aspect. Typically, autologous cells are used. The use of non-autologous mesenchymal stromal cells (MSCs) represents an interesting alternative. Nevertheless, non-autologous, differentiated MSCs may trigger an undesired immune response, hampering bone regeneration. The aim of this study was to unravel the influence of the immune response on endochondral bone regeneration, when using xenogeneic (human) or allogeneic (Dark Agouti) MSCs. To this end, chondrogenically differentiated MSCs embedded in a collagen carrier were implanted in critical size femoral defects of immunocompetent Brown Norway rats. Control groups were included with syngeneic/autologous (Brown Norway) MSCs or a cell-free carrier. The amount of neo-bone formation was proportional to the degree of host-donor relatedness, as no full bridging of the defect was observed in the xenogeneic group whereas 2/8 and 7/7 bridges occurred in the allogeneic and the syngeneic group, respectively. One week post-implantation, the xenogeneic grafts were invaded by pro-inflammatory macrophages, T lymphocytes, which persisted after 12 weeks, and anti-human antibodies were developed. The immune response toward the allogeneic graft was comparable to the one evoked by the syngeneic implants, aside from an increased production of alloantibodies, which might be responsible for the more heterogeneous bone formation. Our results demonstrate for the first time the feasibility of using non-autologous MSC-derived chondrocytes to elicit endochondral bone regeneration in vivo. Nevertheless, the pronounced immune response and the limited bone formation observed in the xenogeneic group undermine the clinical relevance of this group. On the contrary, although further research on how to achieve robust bone formation with allogeneic cells is needed, they may represent an alternative to autologous transplantation.
AB - Mimicking endochondral bone formation is a promising strategy for bone regeneration. To become a successful therapy, the cell source is a crucial translational aspect. Typically, autologous cells are used. The use of non-autologous mesenchymal stromal cells (MSCs) represents an interesting alternative. Nevertheless, non-autologous, differentiated MSCs may trigger an undesired immune response, hampering bone regeneration. The aim of this study was to unravel the influence of the immune response on endochondral bone regeneration, when using xenogeneic (human) or allogeneic (Dark Agouti) MSCs. To this end, chondrogenically differentiated MSCs embedded in a collagen carrier were implanted in critical size femoral defects of immunocompetent Brown Norway rats. Control groups were included with syngeneic/autologous (Brown Norway) MSCs or a cell-free carrier. The amount of neo-bone formation was proportional to the degree of host-donor relatedness, as no full bridging of the defect was observed in the xenogeneic group whereas 2/8 and 7/7 bridges occurred in the allogeneic and the syngeneic group, respectively. One week post-implantation, the xenogeneic grafts were invaded by pro-inflammatory macrophages, T lymphocytes, which persisted after 12 weeks, and anti-human antibodies were developed. The immune response toward the allogeneic graft was comparable to the one evoked by the syngeneic implants, aside from an increased production of alloantibodies, which might be responsible for the more heterogeneous bone formation. Our results demonstrate for the first time the feasibility of using non-autologous MSC-derived chondrocytes to elicit endochondral bone regeneration in vivo. Nevertheless, the pronounced immune response and the limited bone formation observed in the xenogeneic group undermine the clinical relevance of this group. On the contrary, although further research on how to achieve robust bone formation with allogeneic cells is needed, they may represent an alternative to autologous transplantation.
KW - MSCs
KW - adaptive and innate immune response
KW - allograft
KW - bone regeneration
KW - chondrogenic differentiation
KW - endochondral bone formation
KW - graft rejection
KW - xenograft
UR - http://www.scopus.com/inward/record.url?scp=85088438564&partnerID=8YFLogxK
M3 - Article
C2 - 32733861
SN - 2296-4185
VL - 8
SP - 1
EP - 14
JO - Frontiers in bioengineering and biotechnology
JF - Frontiers in bioengineering and biotechnology
M1 - 651
ER -