Immune Modulation by Transplanted Calcium Phosphate Biomaterials and Human Mesenchymal Stromal Cells in Bone Regeneration

Abstract

A wide variety of biomaterials have been developed as both stabilizing structures for the injured bone and inducers of bone neoformation. They differ in chemical composition, shape, porosity, and mechanical properties. The most extensively employed and studied subset of bioceramics are calcium phosphate materials (CaPs). These materials, when transplanted alongside mesenchymal stem cells (MSCs), lead to ectopic (intramuscular and subcutaneous) and orthotopic bone formation in preclinical studies, and effective fracture healing in clinical trials. Human MSC transplantation in pre-clinical and clinical trials reveals very low engraftment in spite of successful clinical outcomes and their therapeutic actions are thought to be primarily through paracrine mechanisms. The beneficial role of transplanted MSC could rely on their strong immunomodulatory effect since, even without long-term engraftment, they have the ability to alter both the innate and adaptive immune response which is critical to facilitate new bone formation. This study presents the current knowledge of the immune response to the implantation of CaP biomaterials alone or in combination with MSC. In particular the central role of monocyte-derived cells, both macrophages and osteoclasts, in MSC-CaP mediated bone formation is emphasized. Biomaterial properties, such as macroporosity and surface microstructure, dictate the host response, and the ultimate bone healing cascade. Understanding intercellular communications throughout the inflammation, its resolution and the bone regeneration phase, is crucial to improve the current therapeutic strategies or develop new approaches.

Osteogenic Differentiation of Human Adipose Tissue-Derived MSCs by Non-Toxic Calcium Poly(ethylene phosphate)s

“…One of the most promising approaches involves the use of mesenchymal stem cells (MSCs) that are seeded into 3D scaffolds and induce bone generation by osteoinductive cues [1,[4][5][6][7]. The design of such 3D scaffolds as a bone void filler can be implemented at the interface of organic chemistry, polymer chemistry, material science and cell biology by the development of the composites containing biodegradable synthetic polymers and calcium phosphates [8][9][10][11].…”

Costimulatory Effect of Rough Calcium Phosphate Coating and Blood Mononuclear Cells on Adipose-Derived Mesenchymal Stem Cells In Vitro as a Model of In Vivo Tissue Repair

“…[ 18 ] and secrete multiple cytokines and chemokines [ 17 ]. At the same time, little is known about the tissue origin (e.g., fat, skin, blood) of cells that can initiate angiogenesis and bone formation in subcutaneously implanted materials [ 1 , 9 , 10 , 11 ] without the addition of osteogenic cells or bone growth factors.…”

“…Besides, inorganic biomaterials, mainly CaPs, can induce direct ectopic bone formation without the addition of osteogenic cells or bone growth factors when implanted under the skin or in muscle [ 1 , 9 , 10 , 11 ]; however, the underlying mechanisms remain unclear. At the same time, there have been a few reports stating that CaP scaffolds without cells did not show new bone formation at 8 weeks after subcutaneous implantation [ 12 ].…”

The Osteosarcoma Microenvironment: A Complex but Targetable Ecosystem

“…They also modulate their microenvironment as they secrete components of ECM and a large variety of mitogenic growth factors, cytokines, chemokines, and metalloproteinases (MMPs) [61]. Consequently, MSCs have autocrine and paracrine trophic properties, as their secreted growth factors stimulate cell division and differentiation of MSCs, osteoblasts, and endothelial cells [62]. Furthermore, MSCs also secrete chemokines (C-C motif) ligand 5 (CCL5), stromal derived factor 1 SDF-1 or (C-X-C motif) chemokine 12 CXCL12, interleukin 6 (IL-6), and growth factor vascular endothelial growth factor (VEGF), known, among others, to promote OS growth, metastasis spread, and angiogenesis (reviewed in Reference [63]).…”

“…The secretome of MSCs contains bioactive EVs, which may explain some well-known but unraveled therapeutic roles of MSCs, including their role in bone regeneration [62]. MSC-secreted EVs were shown to bear tumor supportive microRNAs and proteins, but also metabolites such as lactate and glutamate [68].…”