Systemic mesenchymal stem cell administration enhances bone formation in fracture repair but not load-induced bone formation

Abstract

Mesenchymal stem cells (MSC) were shown to support bone regeneration, when they were locally transplanted into poorly healing fractures. The benefit of systemic MSC transplantation is currently less evident. There is consensus that systemically applied MSC are recruited to the site of injury, but it is debated whether they actually support bone formation. Furthermore, the question arises as to whether circulating MSC are recruited only in case of injury or whether they also participate in mechanically induced bone formation.To answer these questions we injected green fluorescent protein (GFP)-labelled MSC into C57BL/6J mice, which were subjected either to a femur osteotomy or to noninvasive mechanical ulna loading to induce bone formation. We detected GFP-labelled MSC in the early (day 10) and late fracture callus (day 21) by immunohistochemistry. Stromal cell-derived factor 1 (SDF-1 or CXCL-12), a key chemokine for stem cell attraction, was strongly expressed by virtually all cells near the osteotomy -indicating that SDF-1 may mediate cell migration to the site of injury. We found no differences in SDF-1 expression between the groups. Micro-computed tomography (µCT) revealed significantly more bone in the callus of the MSC treated mice compared to untreated controls. The bending stiffness of callus was not significantly altered after MSCapplication. In contrast, we failed to detect GFP-labelled MSC in the ulna after non-invasive mechanical loading. Histomorphometry and µCT revealed a significant loadinduced increase in bone formation; however, no further increase was found after MSC administration. Concluding, our results suggest that systemically administered MSC are recruited and support bone formation only in case of injury but not in mechanically induced bone formation.

Low-magnitude high-frequency vibration enhanced mesenchymal stem cell recruitment in osteoporotic fracture healing through the SDF-1/CXCR4 pathway

“…Also, the current finding is consistent with our previous report regarding the in vitro up-regulation of SDF-1 and CXCR4 mRNA expression, as well as the release of SDF-1 in the culture medium after treating MSCs with another form of mechanical LMHFV enhanced MSC SDF-1 in osteoporotic fracture stimulation, low intensity pulsed ultrasound (LIPUS) (Wei et al, 2014). Moreover, recent reports have demonstrated similar findings that transplantation with or without overexpression of SDF-1 would both improve fracture healing (Ho et al, 2015;Rapp et al, 2015). Therefore, much like other forms of mechanical stimulation, LMHFV was shown to be capable of enhancing MSC recruitment to the fracture site; and the SDF-1/CXCR4 signalling pathway was essential during the process.…”

Lgr5‐overexpressing mesenchymal stem cells augment fracture healing through regulation of Wnt/ERK signaling pathways and mitochondrial dynamics

“…MSC-mediated bone repair is promising and has been used in clinical trials for bone regeneration (7,8). However, MSC-based therapeutics are not always efficient during fracture healing, which may rely on experimental models investigated, source of MSCs used, and administration routes applied (9)(10)(11)(12). Therefore, a better understanding of cellular and molecular mechanisms of MSC-mediated bone regeneration is crucial for the development of novel therapeutic strategies for enhanced skeletal repair (13,14).…”

Antitumor Activity of a Mesenchymal Stem Cell Line Stably Secreting a Tumor-Targeted TNF-Related Apoptosis-Inducing Ligand Fusion Protein

“…Treatment started 10 days after tumor cell inoculation when tumors reached ~100 mm 3 . In particular, 4 × 10 6 MSCs were resuspended in 100 μl PBS mixed with 100 IU/ml of heparin (29) and then peritumorally injected (p.t.). During the injections of all cell lines, mice were anesthetized with isoflurane.…”