scholarly journals High expression of BCL6 inhibits the differentiation and development of hematopoietic stem cells and affects the growth and development of chickens

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hongmei Li ◽  
Bowen Hu ◽  
Shang Hu ◽  
Wen Luo ◽  
Donglei Sun ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Mitochondrial Function ◽  
Growth And Development ◽  
Clinical Manifestations ◽  
High Expression ◽  
Ros Production ◽  
Hematopoietic Stem ◽  
Atp Concentration

Abstract Background B-cell CLL/lymphoma 6 (BCL6) is a transcriptional master regulator that represses more than 1200 potential target genes. Our previous study showed that a decline in blood production in runting and stunting syndrome (RSS) affected sex-linked dwarf (SLD) chickens compared to SLD chickens. However, the association between BCL6 gene and hematopoietic function remains unknown in chickens. Methods In this study, we used RSS affected SLD (RSS-SLD) chickens, SLD chickens and normal chickens as research object and overexpression of BCL6 in hematopoietic stem cells (HSCs), to investigate the effect of the BCL6 on differentiation and development of HSCs. Results The results showed that comparison of RSS-SLD chickens with SLD chickens, the BCL6 was highly expressed in RSS-SLD chickens bone marrow. The bone marrow of RSS-SLD chickens was exhausted and red bone marrow was largely replaced by yellow bone marrow, bone density was reduced, and the levels of immature erythrocytes in peripheral blood were increased. At the same time, the hematopoietic function of HSCs decreased in RSS-SLD chickens, which was manifested by a decrease in the hematopoietic growth factors (HGFs) EPO, SCF, TPO, and IL-3, as well as hemoglobin α1 and hemoglobin β expression. Moreover, mitochondrial function in the HSCs of RSS-SLD chickens was damaged, including an increase in ROS production, decrease in ATP concentration, and decrease in mitochondrial membrane potential (ΔΨm). The same results were also observed in SLD chickens compared with normal chickens; however, the symptoms were more serious in RSS-SLD chickens. Additionally, after overexpression of the BCL6 in primary HSCs, the secretion of HGFs (EPO, SCF, TPO and IL-3) was inhibited and the expression of hemoglobin α1 and hemoglobin β was decreased. However, cell proliferation was accelerated, apoptosis was inhibited, and the HSCs entered a cancerous state. The function of mitochondria was also abnormal, ROS production was decreased, and ATP concentration and ΔΨm were increased, which was related to the inhibition of apoptosis of stem cells. Conclusions Taken together, we conclude that the high expression of BCL6 inhibits the differentiation and development of HSCs by affecting mitochondrial function, resulting in impaired growth and development of chickens. Moreover, the abnormal expression of BCL6 might be a cause of the clinical manifestations of chicken comb, pale skin, stunted growth and development, and the tendency to appear RSS in SLD chickens.

Thrombopoietin (TPO) Regulates HIF-1α Level through Generation of Mitochondrial Reactive Oxygen Species (ROS).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3145-3145
Author(s):  
Kozue Yoshida ◽  
Keita Kirito ◽  
Kenneth Kaushansky ◽  
Norio Komatsu
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Mitochondrial Function ◽  
Leukemic Cell ◽  
Complex Iii ◽  
Ros Generation ◽  
Ros Production ◽  
Hematopoietic Stem ◽  
Respiratory Complexes ◽  
Mitochondrial Respiratory

Abstract Hypoxia inducible factor (HIF)-1 is a master transcriptional regulator for adaptation of cells to hypoxia. In addition to hypoxic responses, HIF-1 also plays an important role in the development of hematopoietic stem cells. Genetic deletion of β subunit of HIF-1 causes impairment of hematopoiesis. Culture of hematopoietic stem cells under hypoxic condition induces elevation of HIF-1α , another subunit of HIF-1, and subsequently enhances the growth of these cells. In our previous work we found that thrombopoietin (TPO), an important and non-redundant cytokine required for normal stem cell development, induces HIF-1α elevation in the TPO-dependent human leukemic cell line UT-7/TPO and in Sca-1+/c-kit+/Gr-1- cells (Kirito, K. et.al. Blood 2005). Under normoxic conditions HIF-1α is hydroxylated on proline residues by prolyl hydroxylase (PHD), which leads to its recognition by the von Hippel-Lindau tumor suppressor protein (pVHL), leading to degradation of HIF-1α . Hypoxia inhibits PHD function, blocking ubiquitination of HIF-1α , stabilizing the protein. We found that TPO controls stability of HIF-1α even under normoxic conditions. However, the mechanism by which TPO controls the stability of the protein remains unclear. Recently, several groups have reported that mitochondrial ROS play crucial roles in stabilization of HIF-1α in response to hypoxia. Disruption of mitochondrial function, either by interfering RNA against complex III of the mitochondrial electron transport chain or genetic elimination of cytochrome c, completely abolished the hypoxia-induced HIF-1α response. Based on these findings we hypothesized that ROS might be involved in TPO-induced HIF-1α elevation. To examine our hypothesis, we first tested whether TPO induced ROS production in UT-7/TPO cells using 2′, 7′-dichlorofluorescein diacetate, a redox sensitive fluorescence dye, and found that the hormone clearly induced ROS production in these cells. Next, we analyzed whether TPO-induced ROS generation is required for accumulation of HIF-1α . Pre-treatment of UT-7/TPO cells with the ROS scavenger catalase completely blocked HIF-1α elevation after TPO treatment. Furthermore, diphenylene iodinium (DPI), an inhibitor for ROS generating flavoenzymes including mitochondrial respiratory complexes, also inhibited the effects of TPO on HIF-1α levels. These results indicate that TPO induced HIF-1α activation is mediated by ROS production. To study the molecular pathway(s) by which TPO affects ROS, we tested the effects of ROS blockade on several known TPO-responsive signaling molecules; neither DPI nor catalase affected the activation of JAK2, STAT5, p38-MAPK or p42/p44-ERK induced by TPO, although AKT activation was blocked. Moreover, LY294002, an inhibitor of PI3-kinase and its activation of AKT also blocked of the HIF-1α response to TPO. Finally, inhibition of mitochondrial function in UT-7/TPO cells with rotenone or oligomycin also inhibited TPO-dependent accumulation of HIF-1α without affecting Jak2 activation. In conclusion, we found that TPO regulates HIF-1α levels through activation of ROS generation within mitochondrial respiratory complexes. We speculate that TPO mimics hypoxia by induction of ROS generation at mitochondria and subsequent elevation of HIF-1α , and regulates important genes for metabolisms and survival of hematopoietic stem cells.

scholarly journals Generation of Dyskeratosis Congenita-like Hematopoietic Stem Cells through the Stable Inhibition of DKC1

2021 ◽  
Author(s):  
Carlos Carrascoso-Rubio ◽  
Hidde A. Zittersteijn ◽  
Laura Pintado-Berninches ◽  
Beatriz Fernández-Varas ◽  
M. Luz Lozano ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Bone Marrow Failure ◽  
Clinical Manifestations ◽  
Dyskeratosis Congenita ◽  
Bone Marrow Failure Syndrome ◽  
Hematopoietic Stem ◽  
Human Cd34 ◽  
Cd34 Cells

Abstract Dyskeratosis congenita (DC) is a rare telomere biology disorder, which results in different clinical manifestations, including severe bone marrow failure. To date, the only curative treatment for bone marrow failure in DC patients is allogeneic hematopoietic stem cell transplantation. However due to the toxicity associated to this treatment, improved therapies are recommended for DC patients. Here we aimed at generating DC-like human hematopoietic stem cells in which the efficacy of innovative therapies could be investigated. Because X-linked DC is the most frequent form of the disease and is associated with an impaired expression of DKC1, we have generated DC-like hematopoietic stem cells based on the stable knock-down of DKC1 in human CD34 + cells with lentiviral vectors encoding for DKC1 short hairpin RNAs. At a molecular level, DKC1 -interfered CD34 + cells showed a decreased expression of TERC, as well as a diminished telomerase activity and increased DNA damage, cell senescence and apoptosis. Moreover, DKC1 -interfered human CD34 + cells showed defective clonogenic ability and were incapable of repopulating the hematopoiesis of immunodeficient NSG mice. The development of DC-like hematopoietic stem cells will facilitate the understanding of the molecular and cellular basis of this inherited bone marrow failure syndrome, and will serve as a platform to evaluate the efficacy of new hematopoietic therapies for DC.

scholarly journals Generation of dyskeratosis congenita-like hematopoietic stem cells through the stable inhibition of DKC1

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Carlos Carrascoso-Rubio ◽  
Hidde A. Zittersteijn ◽  
Laura Pintado-Berninches ◽  
Beatriz Fernández-Varas ◽  
M. Luz Lozano ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Bone Marrow Failure ◽  
Clinical Manifestations ◽  
Dyskeratosis Congenita ◽  
Bone Marrow Failure Syndrome ◽  
Hematopoietic Stem ◽  
Human Cd34 ◽  
Telomere Biology

AbstractDyskeratosis congenita (DC) is a rare telomere biology disorder, which results in different clinical manifestations, including severe bone marrow failure. To date, the only curative treatment for the bone marrow failure in DC patients is allogeneic hematopoietic stem cell transplantation. However, due to the toxicity associated to this treatment, improved therapies are recommended for DC patients. Here, we aimed at generating DC-like human hematopoietic stem cells in which the efficacy of innovative therapies could be investigated. Because X-linked DC is the most frequent form of the disease and is associated with an impaired expression of DKC1, we have generated DC-like hematopoietic stem cells based on the stable knock-down of DKC1 in human CD34+ cells with lentiviral vectors encoding for DKC1 short hairpin RNAs. At a molecular level, DKC1-interfered CD34+ cells showed a decreased expression of TERC, as well as a diminished telomerase activity and increased DNA damage, cell senescence, and apoptosis. Moreover, DKC1-interfered human CD34+ cells showed defective clonogenic ability and were incapable of repopulating the hematopoiesis of immunodeficient NSG mice. The development of DC-like hematopoietic stem cells will facilitate the understanding of the molecular and cellular basis of this inherited bone marrow failure syndrome and will serve as a platform to evaluate the efficacy of new hematopoietic therapies for DC.

scholarly journals Generation of Dyskeratosis Congenita-like Hematopoietic Stem Cells through the Stable Inhibition of DKC1

2020 ◽  
Author(s):  
Carlos Carrascoso-Rubio ◽  
Hidde A. Zittersteijn ◽  
Laura Pintado-Berninches ◽  
Beatriz Fernández-Varas ◽  
M. Luz Lozano ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Bone Marrow Failure ◽  
Clinical Manifestations ◽  
Dyskeratosis Congenita ◽  
Bone Marrow Failure Syndrome ◽  
Hematopoietic Stem ◽  
Human Cd34 ◽  
Telomere Biology

Abstract Dyskeratosis congenita (DC) is a rare telomere biology disorder, which results in different clinical manifestations, including severe bone marrow failure. To date, the only curative treatment for bone marrow failure in DC patients is allogeneic hematopoietic stem cell transplantation. However due to the toxicity associated to this treatment, improved therapies are recommended for DC patients. Here we aimed at generating DC-like human hematopoietic stem cells in which the efficacy of innovative therapies could be investigated. Because X-linked DC is the most frequent form of the disease and is associated with an impaired expression of DKC1, we have generated DC-like hematopoietic stem cells based on the stable knock-down of DKC1 in human CD34+ cells with lentiviral vectors encoding for DKC1 short hairpin RNAs. At a molecular level, DKC1-interfered CD34+ cells showed a decreased expression of TERC, as well as a diminished telomerase activity and increased DNA damage, cell senescence and apoptosis. Moreover, DKC1-interfered human CD34+ cells showed defective clonogenic ability and were incapable of repopulating the hematopoiesis of immunodeficient NSG mice. The development of DC-like hematopoietic stem cells will facilitate the understanding of the molecular and cellular basis of this inherited bone marrow failure syndrome, and will serve as a platform to evaluate the efficacy of new hematopoietic therapies for DC.

The Impact of Age and Gender on Hematopoietic Stem Cells and Immune Contexture of the Bone Marrow Microenvironment

2020 ◽  
pp. 1-6
Author(s):  
Rebar N. Mohammed
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Immune Cells ◽  
Absolute Number ◽  
Cell Number ◽  
Hematopoietic Stem ◽  
The Absolute ◽  
And Gender ◽  
The Impact

Hematopoietic stem cells (HSCs) are a rare population of cells that reside mainly in the bone marrow and are capable of generating and fulfilling the entire hematopoietic system upon differentiation. Thirty-six healthy donors, attending the HSCT center to donate their bone marrow, were categorized according to their age into child (0–12 years), adolescence (13–18 years), and adult (19–59 years) groups, and gender into male and female groups. Then, the absolute number of HSCs and mature immune cells in their harvested bone marrow was investigated. Here, we report that the absolute cell number can vary considerably based on the age of the healthy donor, and the number of both HSCs and immune cells declines with advancing age. The gender of the donor (male or female) did not have any impact on the number of the HSCs and immune cells in the bone marrow. In conclusion, since the number of HSCs plays a pivotal role in the clinical outcome of allogeneic HSC transplantations, identifying a younger donor regardless the gender is critical.

scholarly journals Influence of height on endothelial maintenance activity: a narrative review

2021 ◽  
Vol 26 (1) ◽  
Author(s):  
Yuji Shimizu ◽  
Takahiro Maeda
Keyword(s):  
Risk Factors ◽  
Cardiovascular Disease ◽  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Inverse Association ◽  
Hematopoietic Stem ◽  
Genetic Characteristics ◽  
Maintenance Activity ◽  
Marrow Activity

AbstractRecent studies have revealed an inverse association between height and cardiovascular disease. However, the background mechanism of this association has not yet been clarified. Height has also been reported to be positively associated with cancer. Therefore, well-known cardiovascular risk factors, such as increased oxidative stress and chronic inflammation, are not the best explanations for this inverse association because these risk factors are also related to cancer. However, impaired blood flow is the main pathological problem in cardiovascular disease, while glowing feeding vessels (angiogenesis) are the main characteristic of cancer pathologies. Therefore, endothelial maintenance activity, especially for the productivity of hematopoietic stem cells such as CD34-positive cells, could be associated with the height of an individual because this cell contributes not only to the progression of atherosclerosis but also to the development of angiogenesis. In addition, recent studies have also revealed a close connection between bone marrow activity and endothelial maintenance; bone marrow-derived hematopoietic stem cells contribute towards endothelial maintenance. Since the absolute volume of bone marrow is positively associated with height, height could influence endothelial maintenance activity. Based on these hypotheses, we performed several studies. The aim of this review is not only to discuss the association between height and bone marrow activity, but also to describe the potential mechanism underlying endothelial maintenance. In addition, this review also aims to explain some of the reasons that implicate hypertension as a major risk factor for stroke among the Japanese population. The review also aims to clarify the anthropological reasons behind the high risk of atherosclerosis progression in Japanese individuals with acquired genetic characteristics.

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