Atorvastatin enhances endothelial cell function in posttransplant poor graft function

Abstract

Key Points• Dysfunctional BM EPCs were found in subjects with PGF postallotransplant.• BM EPCs from subjects with PGF were enhanced by atorvastatin through downregulation of the p38 MAPK pathway.Poor graft function (PGF) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Murine studies suggest that endothelial progenitor cells (EPCs) are preferential supporting cells for hematopoietic stem cells in the bone marrow (BM) microenvironment. Our previous work found that a reduced number of BM EPCs was an independent risk factor for the occurrence of PGF after allo-HSCT. However, little is known about the functional role of BM EPCs and how to improve impaired BM EPCs in PGF. In the current study, we evaluated the function of BM EPCs in subjects with PGF postallotransplant. Moreover, we investigated whether atorvastatin could enhance the number and function of BM EPCs derived from subjects with PGF in vitro. Dysfunctional BM EPCs, which were characterized by impaired proliferation, migration, angiogenesis, and higher levels of reactive oxygen species and apoptosis, were revealed in subjects with PGF. Activation of p38 and its downstream transcription factor cyclic adenosine monophosphate-responsive element-binding protein were detected in BM EPCs from subjects with PGF. Furthermore, the number and function of BM EPCs derived from subjects with PGF were enhanced by atorvastatin treatment in vitro through downregulation of the p38 MAPK pathway. In summary, dysfunctional BM EPCs were observed in subjects with PGF. Atorvastatin treatment in vitro quantitatively and functionally improved BM EPCs derived from subjects with PGF through downregulation of the p38 MAPK pathway. These data indicate that atorvastatin represents a promising therapeutic approach for repairing impaired BM EPCs in subjects with PGF postallotransplant. (Blood. 2016;128(25):2988-2999

N‐acetyl‐L‐cysteine improves bone marrow endothelial progenitor cells in prolonged isolated thrombocytopenia patients post allogeneic hematopoietic stem cell transplantation

“…Prolonged isolated thrombocytopenia was defined as the engraftment of all peripheral blood cell lines (absolute neutrophil cells (ANCs) >0.5 × 10 9 /L and hemoglobin (Hb) >70 g/L without transfusion support) other than a PLT count less than 20 × 10 9 /L or a dependence on PLT transfusions for more than 60 days following allo‐HSCT in the presence of complete donor chimerism. Good graft function was characterized by ANCs >0.5 × 10 9 /L for 3 consecutive days, a PLT count >20 × 10 9 /L for 7 consecutive days, and Hb >70 g/L without transfusion support beyond day +28 post‐HSCT. Patients with evidence of poor graft function, severe G v HD including III‐IV acute G v HD and severe chronic G v HD or hematologic relapse following allo‐HSCT were excluded.…”

“…Good graft function was characterized by ANCs >0.5 × 10 9 /L for 3 consecutive days, a PLT count >20 × 10 9 /L for 7 consecutive days, and Hb >70 g/L without transfusion support beyond day +28 post‐HSCT. Patients with evidence of poor graft function, severe G v HD including III‐IV acute G v HD and severe chronic G v HD or hematologic relapse following allo‐HSCT were excluded. Chimerism analyses were performed using DNA fingerprinting for short tandem repeats in blood samples and/or fluorescence in situ chromosomal hybridization in BM samples .…”

“…As previously described, cell apoptosis was assessed using an Annexin‐V and 7‐amino‐actinomycin D (7‐AAD) apoptosis detection kit (Becton Dickinson). The mean fluorescence intensity of the intracellular ROS in the BM EPCs was analyzed following staining with 2ʹ,7ʹ ‐dichlorofluorescence diacetate (DCFH‐DA, Byotimes, China) using a BD LSRFortessa (Becton Dickinson).…”

Aberrant T cell responses in the bone marrow microenvironment of patients with poor graft function after allogeneic hematopoietic stem cell transplantation

“…Good graft function [9–12, 17, 34] was characterized by an absolute neutrophil cell (ANC) count >0.5 × 10 9 /L for 3 consecutive days, platelet (PLT) count >20 × 10 9 /L for 7 consecutive days, and hemoglobin (Hb) level >70 g/L without transfusion support beyond day +28 post-HSCT. Poor graft function [9–12, 17] was defined as a hypo- or aplastic BM with 2 or 3 of the following characteristics: (1) ANC ≤ 0.5 × 10 9 /L; (2) PLT ≤ 20 × 10 9 /L; and/or (3) hemoglobin concentration ≤70 g/L for at least 3 consecutive days after day +28 post-HSCT or in accordance with platelet and/or red blood cell (RBC) transfusion and/or G-CSF support requirement. All RBC and PLT transfused to the patients post-HSCT were gamma irradiated.…”

“…Additionally, PGF patients demonstrate defective BM EPCs, endosteal cells, and perivascular cells in the BM microenvironment [10, 11]. Moreover, atorvastatin may improve the ability of impaired BM EPCs to support HSCs in PGF patients, although these findings were not statistically significant, as determined by colony-forming unit plating efficiency in vitro [12]. Together, these data appear to suggest that the impaired BM microenvironment may hamper the hematopoietic reconstitution of successfully engrafted donor HSCs, ultimately leading to the occurrence of PGF post-allo-HSCT.…”