In patients with corticosteroid induced osteonecrosis of

In patients with corticosteroid-induced osteonecrosis of the femoral head, Wang et al. found that bone repair is limited due to the low proliferation ability of BMSCs (Wang et al., 2008). The altered function of BMSCs may be responsible for the pathogenesis and progression of osteonecrosis. In contrast, the osteogenic abilities of BMSCs in SCD patients are not defective either in vitro or in vivo. However, BMSCs do not appear to prevent osteonecrosis in SCD patients, suggesting that BMSCs cannot migrate to the injury site (Hernigou et al., 2006; Poignard et al., 2012). Indeed, injured tissues express specific receptors or ligands that trigger the mobilization of BMSCs into circulation and facilitate the trafficking, adhesion and infiltration of BMSCs to damaged tissues through a mechanism that is similar to the recruitment of leukocytes to sites of inflammation (Fong et al., 2011; Maumus et al., 2011). In SCD, these mechanisms seem to be defective because sickled RBCs block blood flow and, consequently, the supply of BMSCs. Core decompression (either in combination with or without autologous BM grafting) is classically used to delay the progression of osteonecrosis. Core decompression reduces mechanical stress and enhances bone repair, but bone reconstruction remains incomplete (Gangji et al., 2004). One explanation is the small number of bone progenitor Prostaglandin E2 present in the femoral head and the trochanteric region, especially in patients with non-traumatic or corticosteroid-induced osteonecrosis (Hernigou et al., 1999). Decompression is more effective when combined with autologous BM grafting. Nevertheless, this approach is only successful during the early stages of the disease, probably due to the small number of BMSCs in the BM concentrate (0.001–0.01%) (Hernigou & Beaujean, 2002). The treatment of osteonecrosis is not standardized in SCD patients. Recently, after a mean follow-up of three years, decompression combined with physical therapy (i.e., non-surgical treatment, such as electrical stimulation or physiotherapy) did not result in a better clinical outcome compared with physical therapy alone in patients with SCD (Marti-Carvajal et al., 2012). We show here that the BMSCs from SCD patients may be very valuable for the treatment of osteonecrosis (Kon et al., 2012). Their easy isolation and expansion could provide a large number of osteoblastic progenitors, which could limit the number of complications related to anesthesia and surgery in the SCD patients. Expanded BMSC therapy is a promising approach to treat bone disorders in SCD.
Conclusions In SCD patients with osteonecrosis, the transplantation of a high number of osteoprogenitor cells into the hip is associated with a good outcome (Hernigou et al., 2009). According to our findings, SCD patients with osteonecrosis seem to be excellent candidates for surgery by core decompression combined with cell therapy involving autologous concentrated BM (Hernigou & Beaujean, 2002). We demonstrated here that SCD patients have a higher frequency of CFE values in the BM in a larger patient data based. Given that the BMSCs could be expanded in vitro and retained their functional osteogenic capacities in vitro and in vivo, we suggest that BMSCs isolated from SCD patients can be used clinically in cell therapy approaches. Such an approach has two key benefits: it limits the risk of anesthesia in this disease by facilitating the treatment of several lesions in the same procedure and increases the number of osteoprogenitor cells at the site of osteonecrosis. This work provides important preclinical data that is necessary for the clinical application of expanded stromal Cells for advanced therapies and medical products.
Acknowledgments
Introduction Despite recent advances in the field of oncology, the most common primary malignant brain tumor in adults, glioblastoma multiforme (GBM), still carries a dismal prognosis 1. Its median survival remains just 12–15months (Brandes and Fiorentino, 1996; Laquintana et al., 2009). This is mainly due to the infiltrative nature of GBM, which hampers complete surgical resection, and the limited number of available anticancer agents that can effectively cross the blood brain barrier (BBB) and reach infiltrative tumor foci (Laquintana et al., 2009). In this context, a novel platform of neural stem cell (NSC)-based targeted therapy towards disseminated tumor in the brain has emerged as a promising therapeutic modality (Ahmed et al., 2010; Ahmed et al., 2011a; Ahmed & Lesniak, 2011; Young et al., 2014; Gage & Temple, 2013; Aboody et al., 2013). NSCs are self-renewing, multipotent cells that have the potential to differentiate into the three fundamental types of central nervous system (CNS) cells: neurons, astrocytes, and oligodendrocytes. Three main intrinsic properties of NSCs that make them invaluable carriers of therapeutic payloads have so far been described. First is their inherent tumor homing capacity, which allows for migration of long distances throughout the brain to effectively target diffuse tumor burdens (Aboody et al., 2000; Benedetti et al., 2000). Second is their ability to function as targeted cell carriers (Ahmed et al., 2011a; Ahmed et al., 2013; Auffinger et al., 2013; Thaci et al., 2012), which allows them to be genetically engineered to express increased levels of therapeutic proteins (Yip et al., 2003; Shah et al., 2005). In addition, they can be loaded with selective tumor-targeting agents (i.e. drugs, nanoparticles, oncolytic virus), while maintaining their tumor homing ability (Yip et al., 2003; Shah et al., 2005). Third is their intrinsic immunosuppressive properties, which allow them to effectively deliver therapeutic payloads to infiltrative tumor areas while providing protection from the host immunosurveillance (Ahmed et al., 2013; Mader et al., 2009; Ahmed et al., 2011b). After extensive preclinical evaluation, the Food and Drug Administration (FDA) has approved the use of HB1.F3.CD NSCs in a phase I clinical trial for the treatment of recurrent high-grade gliomas (NCT01172964). HB1.F3.CD is a human-derived NSC line that was genetically engineered to express the suicide gene cytosine deaminase (CD), which converts the pro-drug 5-fluorocytosine (5-FC) into the chemotherapy agent fluorouracil (5-FU) (Aboody et al., 2000; Aboody et al., 2006). Our laboratory has also extensively evaluated NSCs as targeted carriers for anti-glioma oncolytic virotherapy and demonstrated that oncolytic virus loaded NSCs can effectively target brain tumor in the preclinical animal model (Ahmed et al., 2011a; Ahmed et al., 2013; Ahmed et al., 2011b).