Clinical impact of circulating CD34-positive cells on bone regeneration and healing

Abstract

Failures in fracture healing after conventional autologous and allogenic bone grafting are mainly due to poor vascularization. To meet the clinical demand, recent attentions in the regeneration and repair of bone have been focused on the use of stem cells such as bone marrow mesenchymal stem cells and circulating skeletal stem cells. Circulating stem cells are currently paid a lot of attention due to their ease of clinical setting and high potential for osteogenesis and angiogenesis. In this report, we focus on the first proof-of-principle experiments demonstrating the collaborative characteristics of circulating CD34(+) cells, known as endothelial and hematopoietic progenitor cell-rich population, which are capable to differentiate into both endothelial cells and osteoblasts. Transplantation of circulating CD34(+) cells provides a favorable environment for fracture healing via angiogenesis/vasculogenesis and osteogenesis, finally leading to functional recovery from fracture. Based on a series of basic studies, we performed a phase 1/2 clinical trial of autologous CD34(+) cell transplantation in patients with tibial or femoral nonunions and reported the safety and efficacy of this novel therapy. In this review, the current concepts and strategies in circulating CD34(+) cell-based therapy and its potential applications for bone repair will be highlighted.

FIG. 1.

Kinetics of CD34⁺ cells in bone fracture. When bone fracture occurred, CD34⁺ cells (endothelial progenitor cell-rich population) are mobilized from bone marrow into peripheral blood, and they are recruited to the fracture site through circulation. Then, recruited CD34⁺ cells at the injured site develop a favorable environment for fracture healing by releasing vascular endothelial growth factor (VEGF) differentiating osteoblasts and endothelial cells. These combined mechanisms finally enhance vasculogenesis/angiogenesis and osteogenesis, leading to accelerate bridging callus formation and functional recovery from fracture. Color images available online at www.liebertpub.com/teb

FIG. 2.

Schema of clinical trial. Based on inclusion and exclusion criteria, patients are selected and registered after informed consent and preregistration examinations to check eligibility. In the pretransplantation period, after leukoapheresis following 5 days granulocyte colony stimulating factor (G-CSF) injection, patient receives magnet sorting of CD34⁺ cells at day 6. Patient receives conventional surgery for the nonunion combined with autologous transplantation of G-CSF-mobilized peripheral blood CD34⁺ cells (10⁶ cells/kg) suspended in atherocollagen gel at day 6. In the post-transplantation period, the efficacy of the treatment is assessed by clinical and radiological healing at each point assessed toward 1 year after the treatment.