scholarly journals Demonstration that Thy(lo) subsets of mouse bone marrow that express high levels of lineage markers are not significant hematopoietic progenitors

Blood ◽  
1994 ◽  
Vol 83 (12) ◽  
pp. 3480-3490
Author(s):  
SJ Morrison ◽  
E Lagasse ◽  
IL Weissman
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Differentiation ◽  
Cell Types ◽  
Lymphoid Cells ◽  
Mouse Bone Marrow ◽  
Hematopoietic Stem ◽  
B Lineage ◽  
Proliferation Potential

We have been unable to reproduce experiments suggesting the existence of three lineage-restricted progenitor populations from mouse bone marrow. Thy1.1loMac-1+B220+ cells were reported to give rise to greatly expanded numbers of myeloid and lymphoid cells, while Thy1.1loMac- 1+B220- and Thy1.1loMac-1-B220+ cells were reported to be highly proliferative myeloid and B-lineage-restricted progenitors, respectively. Both Mac-1+ cell types appear to be much less frequent than previously reported, and we observed no activity consistent with their characterization as committed progenitors of expanded numbers of cells. The original identification of these populations may have resulted from a failure to distinguish bonafide signals from autofluorescent background and nonspecific staining. The progenitor activities originally associated with these populations may have been due to hematopoietic stem cell contamination. This study shows that low levels of Mac-1 are expressed on cells with multipotent progenitor activity. Thy1.1loB220+Mac-1- cells can be purified from bone marrow, but in these experiments they do not give rise to detectable levels of progeny on injection into lethally irradiated mice. Thy1.1loB220+Mac-1- cells appear to be pro-B cells without significant proliferation potential in vivo. The finding that the described populations do not have the reported progenitor activities leaves the pathways of stem cell differentiation open to further study.

scholarly journals Demonstration that Thy(lo) subsets of mouse bone marrow that express high levels of lineage markers are not significant hematopoietic progenitors

Blood ◽  
1994 ◽  
Vol 83 (12) ◽  
pp. 3480-3490 ◽  
Author(s):  
SJ Morrison ◽  
E Lagasse ◽  
IL Weissman
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Differentiation ◽  
Cell Types ◽  
Lymphoid Cells ◽  
Mouse Bone Marrow ◽  
Hematopoietic Stem ◽  
B Lineage ◽  
Proliferation Potential

Abstract We have been unable to reproduce experiments suggesting the existence of three lineage-restricted progenitor populations from mouse bone marrow. Thy1.1loMac-1+B220+ cells were reported to give rise to greatly expanded numbers of myeloid and lymphoid cells, while Thy1.1loMac- 1+B220- and Thy1.1loMac-1-B220+ cells were reported to be highly proliferative myeloid and B-lineage-restricted progenitors, respectively. Both Mac-1+ cell types appear to be much less frequent than previously reported, and we observed no activity consistent with their characterization as committed progenitors of expanded numbers of cells. The original identification of these populations may have resulted from a failure to distinguish bonafide signals from autofluorescent background and nonspecific staining. The progenitor activities originally associated with these populations may have been due to hematopoietic stem cell contamination. This study shows that low levels of Mac-1 are expressed on cells with multipotent progenitor activity. Thy1.1loB220+Mac-1- cells can be purified from bone marrow, but in these experiments they do not give rise to detectable levels of progeny on injection into lethally irradiated mice. Thy1.1loB220+Mac-1- cells appear to be pro-B cells without significant proliferation potential in vivo. The finding that the described populations do not have the reported progenitor activities leaves the pathways of stem cell differentiation open to further study.

Specialized Bone Marrow Endothelium Defines Microdomains for Tumor and Stem Cell Engraftment.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 663-663
Author(s):  
Dorothy A. Sipkins ◽  
Xunbin Wei ◽  
Juwell W. Wu ◽  
Terry K. Means ◽  
Andrew D. Luster ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Cells ◽  
Stem Cell Differentiation ◽  
Multiple Time ◽  
Normal Stem Cell ◽  
Hematopoietic Stem ◽  
Cell Engraftment ◽  
Vascular Beds

Abstract The organization of cellular niches has been shown to play a key role in regulating normal stem cell differentiation and regeneration, yet relatively little is known about the architecture of microenvironments that support malignant proliferation. Using dynamic in vivo confocal and multi-photon imaging, we show that the bone marrow contains unique anatomic regions defined by specialized endothelium. This vasculature expresses the adhesion molecule E-selectin and the chemoattractant SDF-1 in discrete, discontinuous areas that localize the homing and early engraftment of both leukemic and normal primitive hematopoietic cells. Real-time imaging of cell-cell interactions in SCID mice bone marrow was performed after injection of fluorescently-labeled leukemic and other malignant cell lines. Progressive scanning and optical sectioning through the marrow revealed the existence of unique, spatially-restricted vascular domains to which the majority of marrow-homing tumor cells rolled and arrested. Serial imaging of mice on days 3 – 14 demonstrated that leukemic (Nalm-6 pre-B ALL) extravasation and early proliferation were restricted to these vascular beds. To define the molecular basis of these homing interactions, in vivo labeling of key vascular cell adhesion molecules and chemokines using fluorescent antibodies was performed. We observed that while ICAM-1, VCAM-1, PECAM-1 and P-selectin were expressed diffusely throughout the marrow vasculature, the expression of E-selectin and the chemokine receptor CXCR4 ligand SDF-1 was distinctly limited to vessels that supported leukemic cell engraftment. In vivo co-localization experiments confirmed Nalm-6 binding was restricted to vascular beds expressing both E-selectin and SDF-1. In functional studies, disruption of E-selection had a modest effect on leukemic homing (<20% diminution), while pharmacologic blockade of CXCR4 decreased Nalm-6 binding to vessels by approximately 80%. To explore the normal function of this vascular niche, we next examined whether benign primitive hematopoietic cells might preferentially home to these same vascular microdomains. Fluorescently-labeled stem and progenitor cells (HSPC) isolated from donor balb/c mice were injected into recipient mice and imaging was performed at multiple time points. HSPC were found to adhere to the BM microvasculature in the same restricted domains. At 70 days post-injection, HSPC had extravasated, were persistent in these perivascular areas and had undergone cell division as assessed by dye dilution. Our findings show that these microdomains serve as vascular portals around which leukemic and hematopoietic stem cells engraft, suggesting that this molecularly distinct vasculature provides both a cancer and normal stem cell niche. Specialized vascular structures therefore appear to delineate a stem cell microenvironment that is exploited by malignancy.

scholarly journals Role of bcl-2 in the Development of Lymphoid Cells From the Hematopoietic Stem Cell

Blood ◽  
1997 ◽  
Vol 89 (3) ◽  
pp. 853-862 ◽  
Author(s):  
Yumi Matsuzaki ◽  
Kei-ichi Nakayama ◽  
Keiko Nakayama ◽  
Takashi Tomita ◽  
Miu Isoda ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Fetal Liver ◽  
Lymphoid Cells ◽  
Mouse Bone Marrow ◽  
Chimeric Mouse ◽  
Hematopoietic Stem

Abstract To investigate the role of bcl-2 in lymphohematopoiesis, a long-term bone marrow reconstitution system was established. Transplantation of 1,000 c-Kit+ Sca-1+ and lineage markers negative cells from bcl-2−/− mouse bone marrow resulted in long-term reconstitution of nonlymphoid cells. However, T cells were totally absent and B-lymphocyte development was severely impaired at a very early stage of differentiation in the chimeric mouse. On the other hand, transplantation of day 14 fetal liver cells from bcl-2−/− mice resulted in generation of both T and B cells in the recipient, albeit transiently. These data suggest that bcl-2 plays a critical role in the development of lymphoid progenitor cells from the hematopoietic stem cell (HSC), but is not essential for the development of nonlymphoid cells and the self-renewal of HSC. In addition, lymphopoiesis from fetal liver HSC appears to be less dependent on bcl-2 than adult bone marrow HSC.

scholarly journals Combined Single-Cell and Spatial Transcriptomics to Deconvolute the Hematopoietic Stem Cell Niche

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 876-876
Author(s):  
Simon Haas ◽  
Chiara Baccin ◽  
Jude Al-Sabah ◽  
Lars Velten ◽  
Steinmetz Lars ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Single Cell ◽  
Hematopoietic Stem Cell ◽  
Transcriptional Profiling ◽  
Stem Cell Differentiation ◽  
Cell Types ◽  
Hematopoietic Stem ◽  
Stem Cell Maintenance ◽  
Hematopoietic Stem Cell Niche

Abstract Coordinated interaction of many cell types is required to facilitate hematopoietic and mesenchymal stem cell maintenance and differentiation in the bone marrow. However, the molecular factors and cell types involved in this complex interplay remain poorly understood. Here we developed a combined single cell and spatial transcriptomics approach to address this problem. Large-scale single-cell transcriptional profiling in conjunction with a multi-layered sorting approach allowed us to generate a complete and evenly sampled transcriptional map of all major bone and bone marrow populations. Our dataset covers all cell types or differentiation trajectories involved in mesenchymal and hematopoietic stem cell differentiation, osteogenesis, adipogenesis, myelopoiesis, erythropoiesis, lymphopoiesis, memory T cell formation as well as bone marrow neural innervation and vascularization at the single cell level. Using this data, we derive fundamental properties of the described cell types, clarify the cellular source of signals affecting stem cell differentiation processes and provide a systems view on putative intercellular interactions. Systematic spatial transcriptomics, using laser-capture microdissection of selected bone marrow niches followed by transcriptional profiling and bioinformatic cellular deconvolution, allowed us to confirm predicted interactions and map the cellular composition of distinct bone marrow niches. Our analyses highlight the importance of pre-adipogenic CXCL12 abundant reticular cells as key niche cells for stem cell maintenance, provides a holistic systems view of the hematopoietic stem cell niche and offers a novel approach to systematically deconvolute the molecular, cellular and spatial composition of complex tissues. Disclosures No relevant conflicts of interest to declare.

scholarly journals Hematopoietic Stem Cell Niche During Homeostasis, Malignancy, and Bone Marrow Transplantation

2021 ◽  
Vol 9 ◽  
Author(s):  
Yan Man ◽  
Xiangmei Yao ◽  
Tonghua Yang ◽  
Yajie Wang
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Hematological Malignancies ◽  
Hematopoietic Cells ◽  
Cell Types ◽  
Hematopoietic Stem ◽  
Hematopoietic Stem Cell Niche ◽  
Bm Niche

Self-renewal and multidirectional differentiation of hematopoietic stem cells (HSCs) are strictly regulated by numerous cellular components and cytokines in the bone marrow (BM) microenvironment. Several cell types that regulate HSC niche have been identified, including both non-hematopoietic cells and HSC-derived cells. Specific changes in the niche composition can result in hematological malignancies. Furthermore, processes such as homing, proliferation, and differentiation of HSCs are strongly controlled by the BM niche and have been reported to be related to the success of hematopoietic stem cell transplantation (HSCT). Single-cell sequencing and in vivo imaging are powerful techniques to study BM microenvironment in hematological malignancies and after HSCT. In this review, we discuss how different components of the BM niche, particularly non-hematopoietic and hematopoietic cells, regulate normal hematopoiesis, and changes in the BM niche in leukemia and after HSCT. We believe that this comprehensive review will provide clues for further research on improving HSCT efficiency and exploring potential therapeutic targets for leukemia.

Recombinant TAT-HOXB4 Protein Promotes Ex Vivo Expansion of Primitive Human Hematopoietic Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2855-2855
Author(s):  
Gorazd Krosl ◽  
Marie-Pier Giard ◽  
Jana Krosl ◽  
R. Keith Humphries ◽  
Guy Sauvageau ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Ex Vivo Expansion ◽  
Cell Populations ◽  
Mouse Bone Marrow ◽  
Hematopoietic Stem

Abstract The clinical application of therapeutic protocols depending on hematopoietic stem cell (HSC) transplantation for long term reconstitution with donor-derived HSCs, particularly in patients previously exposed to intensive radiation or chemo-therapy, or when grafts are purged of infiltrating malignant or alloreactive T cells, can be severely hampered by limited numbers of HSCs in the graft. In mouse bone marrow transplantation models, engineered overexpression of HOXB4 has been one of the most potent stimulator of HSC expansion identified to date. The simple addition of soluble recombinant TAT-HOXB4 protein was also recently reported to enable rapid in vitro expansion of mouse HSCs that retain their in vivo proliferation and differentiation capacity. To test the feasibility of using TAT-HOXB4 as a stimulator of human HSC expansion, we performed a series of experiments using CD34+ populations isolated from healthy volunteers. The CD34+ cell populations were cultured in X-Vivo medium supplemented with Stem Cell Factor (300 ng/mL) and G-CSF (50 ng/mL) in the presence or absence of TAT-HOXB4 protein (50 nmol/L) for 4 days. In response to TAT-HOXB4, total numbers of mononuclear cells demonstrated a modest but distinct 2-fold increase compared to controls. TAT-HOXB4 treatment had the largest proliferation enhancing effect on more primitive cell populations such as CFU-GEMM, BFU-E and BFU-Meg, whose numbers increased 26.5 ± 1.4 fold (mean±S.D.), 2.2 ± 0.7 fold and 2.1 ± 0.2 fold, respectively, over their input values, and 19.1 ± 1.3 fold, 2.7 ± 0.7 and 31 ± 3.4 fold, respectively, compared to growth factor only controls. In response to TAT-HOXB4, the total numbers of CD34+CD38-Lin- cells increased 2.1 ± 0.7 fold above their starting numbers compared to a 1.5 ± 0.5 fold loss of this population in control cultures. HSC numbers were enumerated at the beginning, and after a 4-day TAT-HOXB4 treatment period using a NOD/SCID repopulation assay. In response to 50 nM TAT-HOXB4, NOD/SCID repopulating cell (SRC) numbers increased ~2-fold over their input values, compared to a 9-fold loss in control cultures without TAT-HOXB4. These results show that recombinant TAT-HOXB4 protein has the capacity to rapidly induce ex vivo expansion of primitive human bone marrow populations, and suggest that optimization of treatment conditions will rapidly lead to clinically useful expansion of human HSCs.

Herbal Cocktail Ka-Mi-Kae-Kyuk-Tang Stimulates Mouse Bone Marrow Stem Cell Hematopoiesis and Janus-Activated Kinase 2/Signal Transducer and Activator of Transcription 5 Pathway

2011 ◽  
Vol 39 (06) ◽  
pp. 1235-1252 ◽  
Author(s):  
Jeong-Eun Lee ◽  
Inweon Seo ◽  
Soo-Jin Jeong ◽  
Wonil Koh ◽  
Ji Hoon Jung ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Side Effects ◽  
Binding Activity ◽  
Janus Kinase ◽  
Mouse Bone Marrow ◽  
Signal Transducer ◽  
Drug Induced ◽  
Hematopoietic Stem

Ka-mi-kae-kyuk-tang (KMKKT) is an Oriental herbal medicinal cocktail. Our collaborative team has shown that it has potent anti-angiogenic, anti-cancer and anti-metastatic activities in vivo without observable side effects. We have documented evidence for KMKKT to alleviate drug-induced hematotoxicity in vivo. In the present study, we investigated the mechanistic and signaling events through which KMKKT enhances hematopoiesis, using hematopoietic stem cells (HSCs) isolated from the bone marrow of 8–12 week-old C57BL/6 mice. Our results show that KMKKT significantly increased the expression of the hematopoietic cytokines interleukin (IL)-3, stem cell factor (SCF), granulocyte-macrophage-colony stimulating factor (GM-CSF), thrombopoietin (TPO) and erythropoietin (EPO) at the level of mRNA and secretion in HSCs. KMKKT also increased the expression of c-Kit, a cytokine receptor expressed in HSCs. In addition, KMKKT enhanced phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5), and increased the binding activity of STAT5 to gamma interferon activated sites (GAS) that mediate JAK2 downstream signaling. Furthermore, we found that KMKKT significantly enhanced the growth rate of colony-forming unit granulocyte erythrocyte monocyte macrophages (CFU-GEMM) and burst forming unit erythroid (BFU-E) of mouse HSCs (mHSCs) stimulated by IL-3/EPO. Overall, our results demonstrated that KMKKT alleviated drug-induced side effects through enhanced hematopoiesis, at least in part through cytokine-mediated JAK2/STAT5 signaling.

Diversity, localization and (patho)physiology of mature lymphocyte populations in the bone marrow

Blood ◽  
2021 ◽  
Author(s):  
Christian M. Schürch ◽  
Chiara Caraccio ◽  
Martijn A. Nolte
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Plasma Cells ◽  
Cell Types ◽  
Lymphoid Organ ◽  
Lymphoid Cells ◽  
Term Survival ◽  
Hematopoietic Stem ◽  
Mature Lymphocyte ◽  
Lymphocyte Populations

The bone marrow (BM) is responsible for generating and maintaining lifelong output of blood and immune cells. Besides its key hematopoietic function, the BM acts as an important lymphoid organ, hosting a large variety of mature lymphocyte populations, including B-cells, T-cells, NK(T)-cells and innate lymphoid cells (ILCs). Many of these cell types are thought to only transiently visit the BM, but for others, like plasma cells and memory T-cells, the BM provides supportive niches that promote their long-term survival. Interestingly, accumulating evidence points towards an important role for mature lymphocytes in the regulation of hematopoietic stem cells (HSCs) and hematopoiesis in health and disease. In this review, we describe the diversity, migration, localization and function of mature lymphocyte populations in murine and human BM, focusing on their role in immunity and hematopoiesis. We also address how various BM lymphocyte subsets contribute to the development of aplastic anemia and immune thrombocytopenia, illustrating the complexity of these BM disorders, but also the underlying similarities and differences in their disease pathophysiology. Finally, we summarize the interactions between mature lymphocytes and BM resident cells in HSC transplantation and graft-versus-host disease. A better understanding of the mechanisms by which mature lymphocyte populations regulate BM function will likely improve future therapies for patients with benign and malignant hematological disorders.

scholarly journals Comparison of the Proliferation and Differentiation Potential of Human Urine-, Placenta Decidua Basalis-, and Bone Marrow-Derived Stem Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Chengguang Wu ◽  
Long Chen ◽  
Yi-zhou Huang ◽  
Yongcan Huang ◽  
Ornella Parolini ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Stem Cell Differentiation ◽  
Cell Types ◽  
Stem Cell Marker ◽  
Differentiation Potential ◽  
Multipotent Stem Cells ◽  
Decidua Basalis

Human multipotent stem cell-based therapies have shown remarkable potential in regenerative medicine and tissue engineering applications due to their abilities of self-renewal and differentiation into multiple adult cell types under appropriate conditions. Presently, human multipotent stem cells can be isolated from different sources, but variation among their basic biology can result in suboptimal selection of seed cells in preclinical and clinical research. Thus, the goal of this study was to compare the biological characteristics of multipotent stem cells isolated from human bone marrow, placental decidua basalis, and urine, respectively. First, we found that urine-derived stem cells (USCs) displayed different morphologies compared with other stem cell types. USCs and placenta decidua basalis-derived mesenchymal stem cells (PDB-MSCs) had superior proliferation ability in contrast to bone marrow-derived mesenchymal stem cells (BMSCs); these cells grew to have the highest colony-forming unit (CFU) counts. In phenotypic analysis using flow cytometry, similarity among all stem cell marker expression was found, excluding CD29 and CD105. Regarding stem cell differentiation capability, USCs were observed to have better adipogenic and endothelial abilities as well as vascularization potential compared to BMSCs and PDB-MSCs. As for osteogenic and chondrogenic induction, BMSCs were superior to all three stem cell types. Future therapeutic indications and clinical applications of BMSCs, PDB-MSCs, and USCs should be based on their characteristics, such as growth kinetics and differentiation capabilities.

scholarly journals Early megakaryocyte lineage-committed progenitors in adult mouse bone marrow

2021 ◽  
Author(s):  
Zixian Liu ◽  
Jinhong Wang ◽  
Miner Xie ◽  
Peng Wu ◽  
Yao Ma ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Single Cell ◽  
Pcr Analysis ◽  
Mouse Bone Marrow ◽  
Hematopoietic Stem ◽  
Colony Assay ◽  
Megakaryocyte Progenitors ◽  
Cell Colony

Hematopoietic stem cells (HSCs) have been considered to progressively lose their self-renewal and differentiation potentials prior to the commitment to each blood lineage. However, recent studies have suggested that megakaryocyte progenitors are generated at the level of HSCs. In this study, we newly identified early megakaryocyte lineage-committed progenitors (MgPs) in CD201-CD48- cells and CD48+ cells separated from the CD150+CD34-Kit+Sca-1+Lin- HSC population of the bone marrow in C57BL/6 mice. Single-cell transplantation and single-cell colony assay showed that MgPs, unlike platelet-biased HSCs, had little repopulating potential in vivo, but formed larger megakaryocyte colonies in vitro (on average eight megakaryocytes per colony) than did previously reported megakaryocyte progenitors (MkPs). Single-cell RNA-sequencing supported that these MgPs lie between HSCs and MkPs along the megakaryocyte differentiation pathway. Single-cell colony assay and single-cell RT-PCR analysis suggested the coexpression of CD41 and Pf4 is associated with megakaryocyte colony-forming activity. Single-cell colony assay of a small number of cells generated from single HSCs in culture suggested that MgPs are not direct progeny of HSCs. In this study, we propose a differentiation model in which HSCs give rise to MkPs through MgPs.

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