scholarly journals Sensitivity of hematopoietic stem cells to mitochondrial dysfunction by SdhD gene deletion

2016 ◽  
Vol 7 (12) ◽  
pp. e2516-e2516 ◽  
Author(s):  
José Antonio Bejarano-García ◽  
África Millán-Uclés ◽  
Iván V Rosado ◽  
Luís Ignacio Sánchez-Abarca ◽  
Teresa Caballero-Velázquez ◽  
...  
Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3770-3770
Author(s):  
Morgan A Jones ◽  
Meiling Zhao ◽  
Lu Liu ◽  
Ying Feng ◽  
Adam Ross ◽  
...  

Caudal Type Homeobox 2 (CDX2) is a caudal-related homeobox family transcription factor known to be developmental regulator involved in murine axial elongation and anteroposterior vertebral patterning and cell fate determination in the intestine. In adults, CDX2 expression is restricted to the small intestine and the colon. Interestingly, CDX2 is overexpressed in ~90% of human acute myeloid leukemias and the majority of acute lymphoblastic leukemias. Hence, aberrant expression of CDX2 may play a contributing role in leukemogenesis. The role of CDX2 in normal hematopoietic development is unknown. To assess the role of CDX2 in normal hematopoiesis we characterized hematopoietic development in Cdx2 fl/fl Mx1-Cre+ mice after poly (I:C)-mediated gene deletion compared to wildtype littermates. Under steady state conditions, no significant defects were identified in long-term hematopoietic stem cells (LT-HSCs), multipotent progenitors, myeloid progenitors, or mature cell lineages. To test if long-term hematopoietic stem cells were functionally impaired following Cdx2 deletion, competitive transplantation assays were performed. We found that CDX2 was not required for long-term hematopoietic reconstitution in the competitive transplant setting. Together, these data establish that CDX2 is not required for adult steady state hematopoiesis or LT-HSC function. We then asked whether or not CDX2 was essential for leukemogenesis. To interrogate this, Cdx2 fl/fl Mx1-Cre+, Cdx2 fl/+ Mx1-Cre+, and wildtype littermates were treated with poly (I:C) to facilitate gene deletion or for control purposes. Bone marrow cells from the mice were then transformed using well-established HOXA9/MEIS1 or MLL-AF10 leukemogenesis models. In both systems, Cdx2-deficiency prevented leukemia development, whereas wildtype controls succumbed to leukemia within 200 days. Cdx2 heterozygous knockout animals had a delayed onset of leukemia compared to wildtype animals. Taken together, these data indicate that CDX2 is not required for steady state adult hematopoiesis or LT-HSC function, but is necessary for the development of leukemia. Our findings suggest CDX2 has potential as a novel therapeutic target that could be exploited in the majority of AML and ALL patients across a broad mutational spectrum. The nomination of CDX2 as a key target for the majority of leukemias is significant, as current targeted treatment strategies are limited to only particular patient subsets. Disclosures No relevant conflicts of interest to declare.


2006 ◽  
Author(s):  
Hideyo Hirai ◽  
Pu Zhang ◽  
Tajhal Dayaram ◽  
Christopher Hetherington ◽  
Shin-ichi Mizuno ◽  
...  

Author(s):  
И.Ю. Маклакова ◽  
Д.Ю. Гребнев ◽  
А.П. Ястребов

Цель - изучение влияния сочетанной трансплантации мультипотентных мезенхимальных стромальных (ММСК) и гемопоэтических стволовых клеток (ГСК), выделенных из плаценты, на регенерацию белой и красной пульпы селезенки в физиологических условиях и в условиях воздействия ионизующего излучения. Методика. Эксперименты выполнены белых лабораторных беспородных мышах-самцах. Облучение животных проводилось на гамма-терапевтической установке типа АГАТ-С с радионуклидным источником Co-60 типа ГИК-8-4, поглощенная доза составила 4,0 Гр, мощность поглощенной дозы 20 сГр/мин. Животным опытной группы внутривенно вводились аллогенные ММСК и ГСК соответственно в дозе 6 млн клеток/кг и 330 тыс. клеток/кг, суспендированные в 0,2 мл 0,9% раствора NaCl. Выделение гемопоэтических стволовых клеток осуществлялось методом прямой иммуномагнитной сепарации. Проводили морфометрию лимфоидных фолликулов селезенки (средняя площадь, средняя площадь В-зоны, средняя площадь герминативного центра, средняя площадь T-зоны), а также определялось среднее расстояние между центрами фолликулов и средняя клеточность красной пульпы. Результаты. Показано, что после воздействия ионизирующего излучения на фоне сочетанной трансплантации ММСК и ГСК происходит увеличение размеров лимфоидного фолликула за счет площади B-зоны фолликула, площади герминативного центра фолликула, восстановление содержания лимфобластов, пролимфоцитов и лимфоцитов до значений нормы. На фоне трансплантации ММСК и ГСК в условиях лучевой нагрузки установлено увеличение плотности клеток в красной пульпе селезенки и, как следствие, увеличение расстояния между центрами лимфоидных фолликулов. Увеличение плотности клеток в красной пульпе происходит как за счет увеличения содержания эритроидных клеток, так и за счет увеличения гранулоцитов. Заключение. Проведенные исследования свидетельствуют об эффективности сочетанной трансплантации ММСК и ГСК в отношении основных морфометрических показателей селезенки после воздействия ионизирующего излучения. The purpose of this work was to study the effect of combined transplantation of multipotent mesenchymal stromal (MSCS) and hematopoietic stem cells (HSCs) isolated from the placenta, on the regeneration of white and red pulp of the spleen under physiological conditions and in conditions of exposure to ionizing radiation. Methods. The experiments were performed with laboratory mice-males. We studied the influence of ionizing radiation dose of 4.0 Gy. Animals of the experimental group were intravenously infused into MMSC and GSK respectively at a dose of 6 million cells/kg and 330 thousand cells/kg, suspended in 0.2 ml of 0.9% NaCl solution. The selection of hematopoietic stem cells was carried out using the direct technique of immune magnetic separation. Were studied the following morphometric parameters of the spleen: the average area of lymphoid follicles, the average area of zone of lymphoid follicles, average size of germinal center of lymphoid follicles, average size T-zones of lymphoid follicles, the average distance between the centers of the follicles, the average cellularity of the red pulp. Results. As a result, of research obtained that after exposure to ionizing radiation on the background of combined transplantation of HSC and MSCS there is an increase in size of lymphoid follicle at the expense of area B-zone of the follicle, the area germinative center of the follicle, restoring the content of lymphoblasts and lymphoblasts and lymphocytes to normal values. On the background of transplantation MMSC and GSK in terms of radiation exposure changes and the red pulp of the spleen. The increase in the density of cells in the red pulp of the spleen and, as a consequence, of the increase of the distance between the centers of lymphoid follicles. The increase in the density of cells in the red pulp occurs due to the increase in the content of erythroid cells and by increasing granulocytes. Key words: ionizing radiation, multipotent mesenchymal stromal cells, hematopoietic stem cells, spleen, regeneration. Conclusion. Studies have shown the effectiveness of combined transplantation MSC and GSK in respect of the main morphometric parameters of the spleen after exposure to ionizing radiation.


Sign in / Sign up

Export Citation Format

Share Document