Growth Inhibiting Factors of Hematopoietic Stem Cells Produced by Malignant Cells

2019 ◽  
pp. 143-150
Author(s):  
Martine Guigon ◽  
Albert Najman
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Malignant Cells ◽  
Hematopoietic Stem ◽  
Inhibiting Factors ◽  
Growth Inhibiting

Resistance of Hematopoietic Stem Cells Lacking the KIR Ligand to Autologous NK Cell Attacks in Patients with Acquired Aplastic Anemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2939-2939
Author(s):  
Hiroyuki Maruyama ◽  
Luis J. Espinoza ◽  
Takamasa Katagiri ◽  
Yoshitaka Zaimoku ◽  
Koichi Kashiwase ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Aplastic Anemia ◽  
Nk Cells ◽  
Blood Cells ◽  
Nk Cell ◽  
Gene Repertoire ◽  
Malignant Cells ◽  
Hematopoietic Stem ◽  
Accessory Molecules

Abstract Normal blood cells, including hematopoietic stem cells (HSCs), express KIR ligands (KIR-Ls) to protect themselves from an autologous NK cell attack, and malignant cells lacking KIR-Ls elicit NK cell-mediated killing of themselves. This missing-self mechanism is believed to play an important role in the elimination of malignant cells. However, the mechanisms underlying the killing of KIR-L-lacking malignant cells by NK cells remain unclear due to the heterogeneity of tumor cells in terms of their proliferative capacity, and also because other accessory molecules may be involved in the NK cell attacks, in addition to KIR-Ls. This makes it difficult to clarify the interaction between NK cells and KIR-L-lacking target cells. The lack of class I HLA occurs not only in malignant blood cells, but also in the normal leukocytes of patients with acquired aplastic anemia (AA). These HLA-lacking leukocytes, detectable in 13% of patients with AA, are derived from HSCs that undergo copy number neutral loss of heterozygosity of the short arm of chromosome 6 (6pLOH), and thereby escape the cytotoxic T-cell (CTL) attack against HSCs. The 6pLOH may involve KIR-L loss in some patients, leading to a change in the susceptibility of the affected HSCs to NK cell-mediated killing. Unlike malignant cells, HLA-lacking leukocytes are essentially the same as the wild-type leukocytes, except for the HLA expression. Studying 6pLOH (+) AA patients with leukocytes lacking KIR-Ls should therefore be useful for clarifying the roles of KIR-Ls and other accessory molecules in the target cell killing by NK cells. Screening of 389 patients with AA using flow cytometry and a SNP array analysis revealed that there were HLA-A allele-lacking leukocytes in 60 (15.4%) patients, which included 36 C1/C2 and 24 Bw4/Bw6 heterozygotes. Unexpectedly, a lack of KIR-Ls as a result of 6pUPD was found in five patients (13.9%, C1 missing in two and C2 missing in three) of the 36 C1/C2 heterozygotes and in five (20.8%) of the 24 Bw4/Bw6 heterozygotes, although the proportion of patients lacking a KIR-L-containing haplotype (20.8%) was significantly lower than that of patients lacking a haplotype that did not contain KIR-Ls (79.2%). Moreover, the median percentage of HLA-A-lacking granulocytes in the 10 patients who lacked a KIR-L-containing haplotype (12.4%, 0.44%-50.3%) was significantly lower than that (55.3%, 1.4%-99.4%) in the 26 patients who lacked a haplotype that did not contain KIR-Ls, suggesting that the HSCs lacking KIR-Ls or their progenies are susceptible to autologous NK cells to some extent, but are not eliminated completely. To clarify the mechanisms underlying the HSC resistance to NK cells, we determined the KIR gene repertoire and the haplotype of seven patients whose 6pLOH(+) leukocytes were lacking a KIR-L-containing haplotype. All patients possessed inhibitory KIR genes responsive to corresponding KIR-Ls, a finding that negates the possibility that NK cells failed to undergo licensing in these patients. Although the frequency of the KIR-B haplotype, a haplotype associated with a higher cytotoxic function of NK cells, in the seven patients was lower (14%) than that in Japanese healthy individuals (40.1%), two patients possessed the KIR-B haplotype. Phenotypic analyses of the NK cell subsets defined by anti-2DL1, anti-2DL2/2DL3 and anti-3DL1 antibodies showed that all seven patients had a similar percentage of the eight different NK cell subsets, which included 0.5 to 8% of effector NK cells capable of killing leukocytes lacking corresponding KIR-Ls. The expression level of HLA-E was comparable between HLA-A-lacking and HLA-A-retaining monocytes. The expression of NKG2A on the effector NK cells was also comparable to that of the other NK cell subsets in the 6pLOH(+) patients. Our study demonstrated, for the first time, that HSCs lacking KIR-Ls can evade autologous NK cell attack through an as yet unknown mechanism(s) and can continue to generate blood cells in patients with AA. Disclosures No relevant conflicts of interest to declare.

scholarly journals Some hematopoietic stem cells are more equal than others

2010 ◽  
Vol 207 (6) ◽  
pp. 1127-1130 ◽  
Author(s):  
Hanno Hock
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Hematologic Malignancies ◽  
Routine Clinical Practice ◽  
Malignant Cells ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Continuous Progress ◽  
Basic Biology

Hematopoietic stem cells (HSCs) save lives in routine clinical practice every day, as they are the key element in transplantation-based therapies for hematologic malignancies. The success of clinical stem cell transplantation critically relies on the ability of stem cells to reconstitute the hematopoietic system for many decades after the administration of the powerful chemotherapy and/or irradiation that is required to eradicate malignant cells, but also irreversibly ablates patients’ own blood forming capacity. Surprisingly, despite enormous efforts and continuous progress in the field, our understanding of the basic biology of HSCs is still rather incomplete. Several recent studies substantially refine our understanding of the cells at the very top of the hematopoietic hierarchy, and suggest that we may need to revise the criteria we typically use to identify and define HSCs.

Cell staining for sorting of hematopoietic stem cells (HSC) and myeloid progenitors and isolating RNA from sorted cells

2006 ◽  
Author(s):  
Hideyo Hirai ◽  
Pu Zhang ◽  
Tajhal Dayaram ◽  
Christopher Hetherington ◽  
Shin-ichi Mizuno ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem ◽  
Cell Staining ◽  
Myeloid Progenitors

Activation of regeneration of red and white pulp of the spleen after the combined transplantation of HSC and MSCS in terms of exposure to ionizing radiation

2017 ◽  
pp. 22-27
Author(s):  
И.Ю. Маклакова ◽  
Д.Ю. Гребнев ◽  
А.П. Ястребов
Keyword(s):  
Stem Cells ◽  
Ionizing Radiation ◽  
Hematopoietic Stem Cells ◽  
Morphometric Parameters ◽  
Hematopoietic Stem ◽  
Lymphoid Follicles ◽  
Average Area ◽  
Direct Technique ◽  
Average Size ◽  
Red Pulp

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.

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