Intravenous Application of CD271-selected Mesenchymal Stem Cells During Fracture Healing

Abstract

Objectives Circulating mesenchymal stem cells (MSCs) participate in fracture healing and can be used to enhance fracture healing. This study investigated how CD271-selected MSCs travel in circulation and when it is the optimal time to apply MSCs intravenously during fracture healing. Methods Based on the expression of CD271, MSCs were isolated from human bone marrow and labeled with cypate, a near infrared fluorochrome. A unilateral closed fracture was created at the femur in immunodeficient mice. The cypate-labeled MSCs were injected into the tail vein of the mice at days 1 and 3 after fracture, and were tracked by near infrared imaging. The mice were euthanized at 3 weeks after fracture. Immunohistochemistry was performed to detect human MSCs at the fracture sites. Migration of CD271-selected MSCs, under the influence of stem cell derived factor-1 (SDF-1), was assessed in vitro. Results Intravenously injected at day1, but not day 3, after fracture, CD271-selected MSCs accumulated at the fracture sites significantly and that lasted for at least 7 days. All fractures, with or without MSC injections, healed in 3 weeks. Human cells were localized at the fracture sites in mice by immunohistochemistry. CD271-selected MSCs migrated toward the medium contained SDF-1 in vitro. Conclusions After intravenous injection, CD271-selected MSCs were recruited to fracture sites. The stages of fracture healing influenced the homing of culture-expanded MSCs. In mice, an optimal window of intravenous injection of MSCs was around 24 hours after fracture. Clinical Relevance Intravenous application of MSCs may serve as a practical route to deliver stem cells for the treatment of fracture non-union and delayed union. Levels of evidence Level I

Organ-specific migration of mesenchymal stromal cells: Who, when, where and why?

“…However, there was no detectable difference in callus formation or callus size when compared to PBS-injected controls [64]. Intra-articular injected GFP-labeled MSC were found to integrate in cartilage and were involved in the reparative process of cartilage in osteoarthritic donkeys [54].…”

“…(the low-affinity nerve growth factor receptor) [63] were recruited to the fracture site in injured mice upon intravenous injection [64]. However, there was no detectable difference in callus formation or callus size when compared to PBS-injected controls [64].…”

Effects of Transplanting Bone Marrow Stromal Cells Transfected with CXCL13 on Fracture Healing of Diabetic Rats

“…As one of the preferred cells for various tissue engineered seed cells, BMSCs exert beneficial influence on the fracture healing [23,29,30]. However, diabetes mellitus reduced the BMSCs through various ways.…”

Utilization of Multiphoton Imaging For Real-Time Fate Determination of Mesenchymal Stem Cells in an Immunocompetent Mouse Model

“…Even with the increased interest in these cells, debate exists as to the fate of exogenously administered MSCs, including their mode of action and persistence in vivo [20,21]. Additional factors that complicate these determinations include the use of mouse [11,14,20] vs. human MSCs (hMSCs) [2,3,13,21], as well as the use of immunodeficient [2,3,12,13,16] vs. immunocompetent [9,15,21] mouse models when studying hMSCs. All of these caveats have led to reports of MSCs persisting in vivo for various durations from days [9,20] to weeks [15] after I.V.…”