Mesenchymal Stem Cell Exosomes Promote Growth Plate Repair and Reduce Limb-Length Discrepancy in Young Rats

Abstract

Background: The objective of this study was to examine the therapeutic effects of human mesenchymal stromal/stem cell (MSC) exosomes in a rat model of growth plate injury.Methods: A growth plate defect was surgically created on the distal part of the right femur of 40 female Sprague-Dawley rats. A single intra-articular injection of 100 mg of MSC exosomes in 100 mL of phosphate-buffered saline solution (PBS), or an equivalent volume of PBS alone, was administered to the right knee immediately after surgery. At 4 and 8 weeks posttreatment, limb length was measured with micro-CT, and tissue repair was assessed with histological, immunohistochemical, and histomorphometric analyses.Results: A single injection of MSC exosomes significantly increased limb length from 3.29 ± 0.07 cm at 4 weeks to 3.37 ± 0.11 cm at 8 weeks (p = 0.047). However, no improvement in limb length was observed in the PBS control group. The limblength discrepancy between the involved limb and the contralateral limb in the exosome-treated group was significantly less than the discrepancy in the PBS-treated group at both 4 weeks (2.52% ± 1.30% versus 4.11% ± 0.93%; p = 0.006) and 8 weeks (5.27% ± 2.11% versus 8.06% ± 2.56%; p = 0.016). Consistent with the reduced limb-length discrepancy, the exosome-treated defects displayed significantly more chondrocytes (p < 0.05) and a higher area percentage with deposition of sulphated glycosaminoglycan (p < 0.05) and collagen II (p < 0.05) than PBS-treated defects at 8 weeks. However, bone bridge formation was not inhibited in either group.Conclusions: A single intra-articular injection of MSC exosomes significantly enhanced physeal repair and reduced limblength discrepancy but did not inhibit bone-bridge formation.Clinical Relevance: This proof-of-concept study demonstrates for the first time the potential use of MSC exosomes as a minimally invasive cell-free therapeutic to promote physeal repair and reduce limb-length discrepancy following growth plate injuries.

Disruption of Endochondral Ossification and Extracellular Matrix Maturation in an Ex Vivo Rat Femur Organotypic Slice Model Due to Growth Plate Injury

“…Even though bone bridge formation after a sustained GP injury has long been assumed to be the main reason for bone length discrepancies, recent studies have demonstrated that the formation of a bone bridge may only play a minor role and might only develop when certain areas of the GP are affected [ 33 , 34 , 35 ]. For instance, Wong et al [ 36 ] showed reduced limb length discrepancy despite bone bridge formation when they treated a growth plate injury with mesenchymal stem cell (MSC) exosomes [ 37 ].…”

What’s New in Limb Lengthening and Deformity Correction

“…Wong et al studied the effect of human mesenchymal stem exosomes on damaged growth plates in female Sprague-Dawley rats 58 . Their findings revealed significant improvements in the repair of the damaged physes and a reduction in the magnitude of limb-length discrepancy in the experimental group.…”

Tissue engineering in growth plate cartilage regeneration: Mechanisms to therapeutic strategies

“…Therefore, as a minimally invasive cell-free therapy, MSCs-derived Exos can promote the growth plate cartilage regeneration and reduce limb discrepancy after injury. 98 Another study found that after treatment with BMSCs-derived EVs, the proliferating zone at the growth plate injury site showed flat and self-oriented chondrocytes began to arrange into columnar shapes parallel to the bone growth axis, which is similar to the arragenment of the growth plate cartilage structure. The results showed that BMSCs-EVs have differentiation potential and promoted the formation of correct spatial structure in different growth plate regions, especially in proliferative zone.…”