Efficacy of autologous stem cell-based therapy for osteonecrosis of the femoral head in sickle cell disease: a five-year follow-up study

Stem Cell Research & Therapy, Dec 2015

Introduction Stem cell therapy with bone marrow-derived mononuclear cells (BMMCs) is an option for improving joint function in osteonecrosis of the femoral head (ONFH). Bone marrow-derived mesenchymal stromal cell (MSC) numbers and their osteogenic differentiation are decreased in patients with ONFH. However, whether this decrease also extends to the early stages of ONFH in sickle cell disease (SCD) is still unclear. Methods We conducted a phase I/II, non-controlled study to determine efficacy and safety of BMMC implantation using a minimally invasive technique in SCD patients with ONFH. Eighty-nine patients were recruited and followed up for 60 months after surgery. Clinical and radiographic findings were assessed, and data were completed by in vitro analysis. Results At the final follow-up (60 months) there was a significant improvement in clinical joint symptoms and pain relief as measured by the Harris Hip Score (P = 0.0005). In addition, after the BMMC implantation procedure, radiographic assessment showed disease stabilization and only 3.7 % of the treated patients did not achieve a satisfactory clinical result. The amount of fibroblast colony-forming units was 28.2 ± 13.9 per 1 million BMMCs after concentration. Flow cytometry analysis showed a significantly higher number of hematopoietic stem/endothelial progenitor cell markers in concentrated BMMCs when compared with bone marrow aspirate, indicating an enrichment of these cell types. Isolated MSCs from SCD patients with pre-collapse ONFH maintained the replicative capacity without significant loss of their specific biomolecular characteristics, multi-differentiation potential, and osteogenic differentiation activities. Cytokines and growth factors (interleukin-8, transforming growth factor-beta, stromal cell-derived factor-1alpha and vascular endothelial growth factor) that mediate endogenous bone regeneration were also produced by expanded MSCs from SCD patients. Conclusion The autologous BMMC implantation with a minimally invasive technique resulted in significant pain relief and halted the progression of early stages of ONFH in SCD patients. MSCs from SCD patients display biological properties that may add to the efficiency of surgical treatment in ONFH. In summary, our results indicate that infusion of BMMCs enriched with stem/progenitor cells is a safe and effective treatment for the early stages of ONFH in SCD patients. Trial registration ClinicalTrials.gov NCT02448121; registered 15 May 2015.

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Efficacy of autologous stem cell-based therapy for osteonecrosis of the femoral head in sickle cell disease: a five-year follow-up study

Daltro et al. Stem Cell Research & Therapy Efficacy of autologous stem cell-based therapy for osteonecrosis of the femoral head in sickle cell disease: a five-year follow-up study Gildasio Cerqueira Daltro 0 3 Vitor Fortuna 0 1 Eliane Silva de Souza 1 Marcela Miranda Salles 1 Ana Claudia Carreira 2 Roberto Meyer 1 Songeli Menezes Freire 1 Radovan Borojevic 4 0 Equal contributors 1 Health Science Institute, Federal University of Bahia , Reitor Miguel Calmon Avenue, Salvador, BA 40110-100 , Brazil 2 Cell and Molecular Therapy Center NUCEL-NETCEM, School of Medicine, Internal Medicine Department, and Chemistry Institute, Biochemistry Department, University of São Paulo , São Paulo, SP 05508-900 , Brazil 3 Prof. Edgar Santos Hospital Complex , Salvador, BA 40110-902 , Brazil 4 Petrópolis School of Medicine/Arthur de Sá Earp Introduction: Stem cell therapy with bone marrow-derived mononuclear cells (BMMCs) is an option for improving joint function in osteonecrosis of the femoral head (ONFH). Bone marrow-derived mesenchymal stromal cell (MSC) numbers and their osteogenic differentiation are decreased in patients with ONFH. However, whether this decrease also extends to the early stages of ONFH in sickle cell disease (SCD) is still unclear. Methods: We conducted a phase I/II, non-controlled study to determine efficacy and safety of BMMC implantation using a minimally invasive technique in SCD patients with ONFH. Eighty-nine patients were recruited and followed up for 60 months after surgery. Clinical and radiographic findings were assessed, and data were completed by in vitro analysis. Results: At the final follow-up (60 months) there was a significant improvement in clinical joint symptoms and pain relief as measured by the Harris Hip Score (P = 0.0005). In addition, after the BMMC implantation procedure, radiographic assessment showed disease stabilization and only 3.7 % of the treated patients did not achieve a satisfactory clinical result. The amount of fibroblast colony-forming units was 28.2 ± 13.9 per 1 million BMMCs after concentration. Flow cytometry analysis showed a significantly higher number of hematopoietic stem/endothelial progenitor cell markers in concentrated BMMCs when compared with bone marrow aspirate, indicating an enrichment of these cell types. Isolated MSCs from SCD patients with pre-collapse ONFH maintained the replicative capacity without significant loss of their specific biomolecular characteristics, multi-differentiation potential, and osteogenic differentiation activities. Cytokines and growth factors (interleukin-8, transforming growth factor-beta, stromal cell-derived factor-1alpha and vascular endothelial growth factor) that mediate endogenous bone regeneration were also produced by expanded MSCs from SCD patients. Conclusion: The autologous BMMC implantation with a minimally invasive technique resulted in significant pain relief and halted the progression of early stages of ONFH in SCD patients. MSCs from SCD patients display biological properties that may add to the efficiency of surgical treatment in ONFH. In summary, our results indicate that infusion of BMMCs enriched with stem/progenitor cells is a safe and effective treatment for the early stages of ONFH in SCD patients. Trial registration: ClinicalTrials.gov NCT02448121; registered 15 May 2015. Introduction Sickle cell disease (SCD) is the most common inherited blood disease, with a worldwide distribution. In Brazil, the prevalence of hemoglobin S (HbS) carriers varies from 6 % to 15.7 % among different population groups [ 1 ]. The highest frequency of abnormal hemoglobin and the rate of race admixture, mainly of African descendent, means the presence of hemoglobinopathies is considered a public health problem in northeast Brazil [ 2, 3 ]. Osteonecrosis of the femoral head (ONFH) is a debilitating and severe complication of SCD and its treatment is still a big challenge. Depending upon the particular genotype and severity of the SCD, the prevalence of ONFH ranges from 3 to 50 % among SCD patients [ 4, 5 ]. Osteonecrosis can be viewed as a vascular and bone disease with altered bone remodeling. The combination of vascular and bone pathologies contributes to the development of osteonecrosis, which leads to inadequate bone repair that advances to subchondral fracture [ 6, 7 ]. Patients with SCD experience both large and small vessel occlusions leading to end-organ damage and complications such as ONFH. These vascular occlusion events result from various processes including hypoxia-induced erythrocyte sickling, along with extravascular compression of the intra-osseous blood supply resulting in an imbalance between osteoblast formation and necrosis, which culminates in femoral head infarction [8]. If left untreated, ONFH has a high likelihood of progression to secondary arthrosis in up to 86 % of cases [ 7, 9 ]. Once collapse occurs, total arthroplasty is a possible treatment, but its high rates of infection (...truncated)


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Gildasio Cerqueira Daltro, Vitor Fortuna, Eliane Silva de Souza, Marcela Miranda Salles, Ana Claudia Carreira, Roberto Meyer, Songeli Menezes Freire, Radovan Borojevic. Efficacy of autologous stem cell-based therapy for osteonecrosis of the femoral head in sickle cell disease: a five-year follow-up study, Stem Cell Research & Therapy, 2015, pp. 110, Volume 6, Issue 1, DOI: 10.1186/s13287-015-0105-2