ABSTRACT
BACKGROUND AND OBJECTIVES: Bone marrow mesenchymal stromal cells (BM-MSCs) are key elements of the hematopoietic niche and participate in the regulatory mechanisms of hematopoietic stem cells (HSCs). Hematological diseases can affect MSCs and their functions. However, the dysregulations caused by sickle cell disease (SCD) are not fully elucidated. This work explored changes in BM-MSCs and their relationship with age using sickle cell mice (Townes-SS). MATERIALS AND METHODS: BM-MSCs were isolated from Townes-SS, and control groups 30- and 60-day-old Townes-AA and C57BL/6 J. RESULTS: The BM-MSCs showed no morphological differences in culture and demonstrated a murine MSC-like immunophenotypic profile (Sca-1+, CD29+, CD44+, CD90.2+, CD31-, CD45-, and CD117-). Subsequently, all BM-MSCs were able to differentiate into adipocytes and osteocytes in vitro. Finally, 30-day-old BM-MSCs of Townes-SS showed higher expression of genes related to the maintenance of HSCs (Cxcl12, Vegfa, and Angpt1) and lower expression of pro-inflammatory genes (Tnfa and Il-6). However, 60-day-old BM-MSCs of Townes-SS started to show expression of genes related to reduced HSC maintenance and increased expression of pro-inflammatory genes. CONCLUSION: These results indicates age as a modifying factor of gene expression of BM-MSCs in the context of SCD.
Subject(s)
Anemia, Sickle Cell , Mesenchymal Stem Cells , Humans , Animals , Mice , Bone Marrow , Mice, Inbred C57BL , Hematopoietic Stem Cells/metabolism , Mesenchymal Stem Cells/metabolism , Bone Marrow Cells/metabolism , Cell DifferentiationABSTRACT
BACKGROUND AIMS: Amidst the success of cell therapy for the treatment of onco-hematological diseases, the first recently Food and Drug Administration-approved gene therapy product for patients with transfusion-dependent ß-thalassemia (TDT) indicates the feasibility of gene therapy as curative for genetic hematologic disorders. This work analyzed the current-world scenario of clinical trials involving gene therapy for ß-hemoglobinopathies. METHODS: Eighteen trials for patients with sickle cell disease (SCD) and 24 for patients with TDT were analyzed. RESULTS: Most are phase 1 and 2 trials, funded by the industry and are currently recruiting volunteers. Treatment strategies for both diseases are fetal hemoglobin induction (52.4%); addition of wild-type or therapeutic ß-globin gene (38.1%) and correction of mutations (9,5%). Gene editing (52.4%) and gene addition (40.5%) are the two most used techniques. The United States and France are the countries with the greatest number of clinical trials centers for SCD, with 83.1% and 4.2%, respectively. The United States (41.1%), China (26%) and Italy (6.8%) lead TDT trials centers. CONCLUSIONS: Geographic trial concentration indicates the high costs of this technology, logistical issues and social challenges that need to be overcome for gene therapy to reach low- and middle-income countries where SCD and TDT are prevalent and where they most impact the patient's health.
Subject(s)
Anemia, Sickle Cell , Hemoglobinopathies , Humans , Hemoglobinopathies/genetics , Hemoglobinopathies/therapy , Anemia, Sickle Cell/genetics , Anemia, Sickle Cell/therapy , Cell- and Tissue-Based Therapy , China , Genetic TherapyABSTRACT
From a country with one of the highest SARS-CoV-2 morbidity and mortality rates, Brazil has implemented one of the most successful vaccination programs. Brazil's first model city vaccination program was performed by the CoronaVac vaccine (Sinovac Biotech) in the town of Serrana, São Paulo State. To evaluate the vaccination effect on the SARS-CoV-2 molecular dynamics and clinical outcomes, we performed SARS-CoV-2 molecular surveillance on 4375 complete genomes obtained between June 2020 and April 2022 in this location. This study included the period between the initial SARS-CoV-2 introduction and during the vaccination process. We observed that the SARS-CoV-2 substitution dynamics in Serrana followed the viral molecular epidemiology in Brazil, including the initial identification of the ancestral lineages (B.1.1.28 and B.1.1.33) and epidemic waves of variants of concern (VOC) including the Gamma, Delta, and, more recently, Omicron. Most probably, as a result of the immunization campaign, the mortality during the Gamma and Delta VOC was significantly reduced compared to the rest of Brazil, which was also related to lower morbidity. Our phylogenetic analysis revealed the evolutionary history of the SARS-CoV-2 in this location and showed that multiple introduction events have occurred over time. The evaluation of the COVID-19 clinical outcome revealed that most cases were mild (88.9%, 98.1%, 99.1% to Gamma, Delta, and Omicron, respectively) regardless of the infecting VOC. In conclusion, we observed that vaccination was responsible for reducing the death toll rate and related COVID-19 morbidity, especially during the gamma and Delta VOC; however, it does not prevent the rapid substitution rate and morbidity of the Omicron VOC.
