Trisomy 21 Expands the Megakaryocyte-Erythroid Progenitor Compartment in Human Fetal Liver-Implications for Down Syndrome AMKL.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 563-563 ◽  
Author(s):  
Oliver Tunstall-Pedoe ◽  
Josu de la Fuente ◽  
Phillip R. Bennett ◽  
Nicholas M. Fisk ◽  
Paresh Vyas ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Down Syndrome ◽  
Trisomy 21 ◽  
Fetal Liver ◽  
Fetal Blood ◽  
Fetal Bone ◽  
Cd34 Cells ◽  
Progenitor Compartment ◽  
Gata1 Mutation

Abstract Children with Down syndrome (DS) have a uniquely high frequency of acute megakaryoblastic leukemia (AMKL)- ~500-fold increased compared to children without trisomy 21 (T21). At least two genetic events are required but are not sufficient for DS-AMKL: T21 and N-terminal truncating mutations in the key megakaryocytic transcription factor GATA1. This tight association of T21 with GATA1 mutations and the development of AMKL in a narrow temporal window (fetal life-5yrs) makes DS-AMKL a highly informative model of multi-hit leukemogenesis in which the first steps occur in utero. However, the individual contributions of T21 and mutant GATA1 in the leukemogenesis are unclear. To specifically investigate the role of T21 in DS-AMKL and why leukemia-initiation is confined to fetal (or early post-natal) life we have studied fetal hemopoiesis in DS during the second and third trimester in 16 fetuses (gestational age 15–37 weeks) where an antenatal diagnosis of DS with T21 was made by amniotic fluid fetal cell karyotyping. Samples of fetal blood (n=13), fetal liver (n=9) and fetal bone marrow (n=8) were screened for mutations in the GATA1 gene genomic DNA by DHPLC or direct sequencing (sensitivity of detecting a GATA1 mutation is 1–5% by DHPLC). No GATA1 mutations were detected. This allowed us to study the impact of T21 independent of GATA1 mutation on fetal hemopoiesis. DS fetuses showed marked qualitative and quantitative abnormalities in hemopoiesis. While the total number of CD34+ cells in DS and normal fetal liver were comparable, DS fetuses had a striking increase in bi-potential megakaryocyte-erythroid progenitors (MEP; CD34+CD38+FcgloCD45RA+− 74.4% vs 27.0% of fetal liver CD34+/CD38+ cells. Peripheral blood from all DS fetuses studied compared to normal fetal blood samples showed dysmegakaryopoiesis (abnormally shaped and/or giant platelets and MK fragments), dyserythropoiesis (macrocytes, poikilocytes, basophilic stippling), increased numbers of blast cells and also had an increased percentage of MEPs − 40.3% vs 26.9%. By contrast, there was no difference in the number of MEP nor erythroid or MK lineage morphology in DS fetal bone marrow compared to normal fetal bone marrow. CD34+ cells from DS fetal liver and fetal blood expressed both fl GATA1 and GATA1s mRNA indicating that dysmegakaryopoiesis and erythropoiesis were not due to lack of expression of fl GATA1. These data indicate, for the first time, that T21 by itself profoundly disturbs megakaryopoiesis and erythropoiesis and leads to an increased of frequency of MEP. This has important implications since it provides a testable hypothesis for the role of T21 in the initiating step of AMKL, namely that T21 expands a fetal liver-derived progenitor compartment which forms a substrate upon which GATA1 mutations then confer a further selective advantage.

Abnormalities in the myeloid progenitor compartment in Down syndrome fetal liver precede acquisition of GATA1 mutations

Blood ◽  
2008 ◽  
Vol 112 (12) ◽  
pp. 4507-4511 ◽  
Author(s):  
Oliver Tunstall-Pedoe ◽  
Anindita Roy ◽  
Anastasios Karadimitris ◽  
Josu de la Fuente ◽  
Nicholas M. Fisk ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Fetal Liver ◽  
Testable Hypothesis ◽  
Erythroid Progenitor ◽  
Megakaryoblastic Leukemia ◽  
Myeloid Progenitor ◽  
Cd34 Cells ◽  
Progenitor Compartment ◽  
Normal Controls

Abstract Down syndrome (DS) children have a high frequency of acute megakaryoblastic leukemia (AMKL) in early childhood. At least 2 in utero genetic events are required, although not sufficient, for DS-AMKL: trisomy 21 (T21) and N-terminal–truncating GATA1 mutations. To investigate the role of T21 in DS-AMKL, we compared second trimester hemopoiesis in DS without GATA1 mutations to gestation-matched normal controls. In all DS fetal livers (FLs), but not marrows, megakaryocyte-erythroid progenitor frequency was increased (55.9% ± 4% vs 17.1% ± 3%, CD34+CD38+ cells; P < .001) with common myeloid progenitors (19.6% ± 2% vs 44.0% ± 7%) and granulocyte-monocyte (GM) progenitors (15.8% ± 4% vs 34.5% ± 9%) commensurately reduced. Clonogenicity of DS-FL versus normal FL CD34+ cells was markedly increased (78% ± 7% vs 15% ± 3%) affecting megakaryocyte-erythroid (∼ 7-fold higher) and GM and colony-forming unit–granulocyte, erythrocyte macrophage, megakaryocyte (CFU-GEMM) progenitors. Replating efficiency of CFU-GEMM was also markedly increased. These data indicate that T21 itself profoundly disturbs FL hemopoiesis and they provide a testable hypothesis to explain the increased susceptibility to GATA1 mutations in DS-AMKL and DS-associated transient myeloproliferative disorder.

Trisomy 21 Driven Pro-Inflammatory Signalling in Fetal Bone Marrow May Play a Role in Perturbed B-Lymphopoiesis and Acute Lymphoblastic Leukemia of Down Syndrome

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1206-1206 ◽  
Author(s):  
Sorcha Isabella O'Byrne ◽  
Natalina Elliott ◽  
Gemma Buck ◽  
Siobhan Rice ◽  
David O'Connor ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Down Syndrome ◽  
Trisomy 21 ◽  
Lymphoblastic Leukemia ◽  
B Lymphopoiesis ◽  
Increased Risk ◽  
Cd34 Cells ◽  
Inflammatory Signalling

Introduction: Children with Down syndrome (DS) have a markedly increased risk of acute lymphoblastic leukemia (ALL), suggesting that trisomy 21 (T21) has specific effects on hematopoietic stem and progenitor cell (HSPC) biology in early life. Data from human fetal liver (FL) indicates that T21 alters fetal hematopoiesis, causing multiple defects in lympho-myelopoiesis. The impact of T21 on fetal B lymphopoiesis and how this may underpin the increase in ALL is not well known. We have recently found that fetal bone marrow (FBM) rather than FL is the main site of B lymphopoiesis; with a marked enrichment of fetal-specific progenitors (early lymphoid progenitors, ELP and PreProB progenitors) that lie upstream of adult type ProB progenitors (O'Byrne et al, Blood, in press). Previous preliminary data suggested that B progenitors were also reduced in T21 FBM (Roy et al, Blood. 124, 4331). Aim: To dissect putative molecular mechanisms responsible for the defects in T21 FBM B-lymphopoiesis and its association with childhood DS ALL. Methods: Second trimester human FBM and paediatric ALL samples were obtained from the Human Developmental Biology Resource and UK Childhood Leukaemia Cell Bank respectively. Multiparameter flow cytometry/sorting, transcriptome analysis by RNA-sequencing and microarray, and stromal co-culture assays were used to characterize HSPC and mesenchymal stromal cells (MSC) from normal (NM) disomic (n=21-35) and T21 (n=7-12) human FBM; RNASeq was performed on cytogenetically matched non-DS (n=13) and DS ALL (n=7). Results: In contrast to NM FBM, fetal specific progenitors were virtually absent (CD34+CD10-CD19-CD127+ ELP 2.8±0.4% vs. 0.8±0.4% of CD34+ cells) or very severely reduced (CD34+CD10-CD19+ PreProB 12.8±1 vs 2.6±0.7%) in T21 FBM. This was despite a >4-fold increase in the frequency of immunophenotypic HSC (4.2±1.2% vs 0.9±0.2% of CD34+ cells) and similar frequencies of MPP and LMPP in T21 FBM. As in adult BM, the vast majority of B progenitors in T21 FBM were CD34+CD10+CD19+ ProB progenitors with a frequency (28.8±8.3%) similar to NM FBM (30.3±2.3% of CD34+ cells). Thus, T21 causes a severe block in B-progenitor commitment at the LMPP stage, in tandem with a compensatory expansion of ProB progenitors. Consistent with this, T21 FBM HSC, MPP and LMPP had reduced B cell potential in vitro compared to NM FBM in MS5 co-cultures. RNAseq of NM (n=3) and T21 (n=3) FBM HSPC demonstrated global transcriptomic disruption by T21, with increased gene expression in HSC, MPP, LMPP and ProB progenitors. Cell cycle genes were enriched in T21 ProB progenitors. Despite these functional and global gene expression differences, expression of key B-lineage commitment genes was maintained suggesting the defect in B-lymphopoiesis may be secondary to lineage skewing of multipotent progenitors towards a non-B lymphoid fate and/or mediated by extrinsic factors. GSEA pointed to a role for multiple inflammatory pathways in T21 hematopoiesis with dysregulation of IFNα, IL6 and TGFβ signalling pathways in T21 HSC/LMPP. To investigate the role of the T21 microenvironment, we co-cultured NM HSC, MPP and LMPP with T21 or NM primary FBM MSC. T21 FBM MSC (n=3) had reduced capacity to support B cell differentiation in vitro consistent with perturbation of MSC function by T21. Similar to T21 FBM HSPC, transcriptomic analysis of T21 FBM MSC by microarray showed enrichment for IFNα signalling compared to NM; and T21 HSPC and MSC both showed increased gene expression for IFNα receptors IFNAR1 and IFNAR2, which are encoded on chromosome 21. Since IFNα was undetectable by ELISA of conditioned media from NM and T21 MSC, differences in secreted IFNα from MSC are unlikely to fully explain the increased IFN signalling in T21 HSPC and MSC. This suggests that T21 may drive autocrine rather than paracrine IFN signalling in FBM cells. Finally, RNASeq showed perturbed inflammatory signalling in DS ALL compared to non-DS ALL, suggesting a role for T21-driven inflammatory pathways in the biology of DS ALL. Conclusions: These data show that T21 severely impairs B lymphopoiesis in FBM and is associated with expression of proinflammatory gene expression programs in T21 FBM HSPC and MSC and DS ALL. The compensatory expansion of T21 FBM ProB progenitors, through self-renewal or via an alternative differentiation pathway; with concomitant T21-driven proinflammatory signalling may underpin the increased risk of B progenitor ALL in childhood. Disclosures No relevant conflicts of interest to declare.

scholarly journals Study of the Role of the HSC Niche in HSC Migration from Fetal Liver to Fetal Bone Marrow

2008 ◽  
Vol 22 (S1) ◽  
Author(s):  
Jesús Ciriza ◽  
Dominique Hall ◽  
Shelley Wang ◽  
Tania Carroll ◽  
Marcos García‐Ojeda
Keyword(s):  
Bone Marrow ◽  
Fetal Liver ◽  
Fetal Bone ◽  
Hsc Niche

Hematopoiesis in the Ts65Dn Mouse Model of Down Syndrome (DS) Recapitulates Many Features of Human DS.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1122-1122
Author(s):  
Gina Mundschau ◽  
Sarah Jilani ◽  
Michelle Le Beau ◽  
John Crispino
Keyword(s):  
Down Syndrome ◽  
Mouse Model ◽  
Trisomy 21 ◽  
Fetal Liver ◽  
Hemoglobin Concentration ◽  
Chromosome 16 ◽  
Ts65dn Mouse ◽  
Cd34 Cells ◽  
Complete Blood Counts ◽  
Acute Megakaryocytic Leukemia

Abstract Down syndrome-associated acute megakaryocytic leukemia (DS-AMKL) is a complex malignancy that evolves in hematopoietic progenitors with trisomy 21 that acquire a somatic mutation in the blood transcription factor GATA1. The mechanistic relationship between these two genetic factors that leads to leukemia is poorly understood. In order to study the interplay between trisomy 21 and GATA1 mutations, we are developing a mouse model of this malignancy. The Ts65Dn mouse, which contains a segmental trisomy for mouse chromosome 16, homologous to human 21, has been reported to display several of the cognitive and craniofacial phenotypes seen in humans with DS, but the hematopoietic system has not been assessed as a model for blood development in humans with DS. We have evaluated adult hematopoiesis in the Ts65Dn strain by comparing monthly complete blood counts (CBC) of peripheral blood from 14 trisomic and 20 disomic littermates. Similar to humans with DS, Ts65Dn trisomic mice display persistent erythrocyte macrocytosis, with values at the high end of the normal range. Trisomic mice also harbor decreased numbers of red blood cells, mildly elevated platelet counts, a higher percentage of monocytes and a lower hemoglobin concentration. Interestingly infants with DS frequently display thrombocytosis. In addition, we have characterized fetal liver hematopoiesis in the Ts65Dn strain by FACS analysis of hematopoietic precursors and by performing colony assays. In general, we did not detect any significant differences in erythroid, myeloid, or megakaryocytic colony formation between trisomic or disomic fetuses. Likewise flow cytometry for CD34, TER119, and CD41 demonstrated overall similar numbers of cells in these compartments for Ts65Dn mice and disomic littermates. However, one of seven trisomic embryos displayed a significant increase in the proportion of CD34+ cells with concomitant decrease in both Ter119+ and CD41+ populations. In addition, cells from this fetal liver gave rise to seven-fold and three-fold increases in BFU-E and CFU-Mk colonies respectively, with no change in the CFU-GM. Although the sample size is small, these findings suggest that a subset of Ts65Dn trisomic fetuses exhibit aberrant hematopoiesis. Taken together, our study indicates that the Ts65Dn trisomic mouse may be an excellent model to study human DS hematopoiesis.

Niche Requirements of Transient Leukemia Cells in Down Syndrome

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1753-1753
Author(s):  
Agnieszka A. Wendorff ◽  
Jian Chen ◽  
Yue Li ◽  
Johann K. Hitzler
Keyword(s):  
Bone Marrow ◽  
Down Syndrome ◽  
Growth Factors ◽  
Stromal Cells ◽  
Trisomy 21 ◽  
Conflicts Of Interest ◽  
Fetal Liver ◽  
Cell Contact ◽  
Children With Down Syndrome ◽  
Transient Leukemia

Abstract Abstract 1753 Background. Young children with Down syndrome (DS; constitutional trisomy 21) have a 150-fold higher risk of developing acute myeloid leukemia (AML). Blast cells are detectable in the peripheral blood of approximately 10% of newborns with DS; these indicate the frequent presence of a preleukemic disorder termed transient leukemia (TL)/transient myeloproliferative disorder (TMD). This disorder of fetal hematopoiesis is triggered by somatic mutations of the hematopoietic transcription factor GATA1 exclusively in the context of cellular trisomy 21. The majority of TL cases undergo spontaneous resolution by unknown mechanisms. In contrast, approximately 1 of 5 cases progress to AML within a defined postnatal window (first 4 years of life). We hypothesized that the resolution of TL results from the absence of essential environmental cues following the developmental transition from prenatal fetal liver (FL) hematopoiesis to postnatal blood cell formation in the bone marrow (BM). We previously observed that primary blasts of human TL lack the proliferative expansion in the bone marrow environment of xenotransplant recipients that is observed for blasts of DS-AML. Consequently, we aimed to identify the signals provided by the FL niche that support the survival and proliferation of human TL cells. Methods and Results. To determine the differential impact of the hematopoietic niche provided by FL and postnatal BM on TL cells, we cultured primary human TL cells on murine stromal cell lines that were derived either from FL (AFT024) or adult BM (MS-5). The absolute number of primary TL cells increased >80-fold during culture on FL-derived stromal cells for 2 weeks. In contrast, BM-derived MS-5 stromal cells supported only a moderate expansion (<10-fold), which was associated with enhanced induction of apoptotic cell death and evidence of partial myeloid differentiation. Direct interaction between TL and stromal cells – acting co-operatively with soluble growth factors – appears indispensable for the maintenance of TL cell survival and stimulation of proliferation. Functional studies identified the very late antigen-4 [VLA-4 (CD49d)]/vascular cell adhesion molecule-1 (VCAM-1) binding partners as putative mediator of this interaction. Furthermore, insulin-like growth factor 2 (IGF-2) supplementation augmented the proliferation of TL cells specifically in the context of the FL niche. Neither IGF-2 alone or in combination with BM-derived stroma promoted expansion of TL cells. Work currently underway aims at identification of additional molecular pathways involved in TL-cell regulation, including elucidating the potential role of Notch signaling in development and maintenance of TL cells. Conclusions. Cooperative signals that are preferentially provided by the hematopoietic environment of the fetal liver support the survival and proliferation of human TL cells. These signals consist of a combination of cell-cell contact, in part mediated by VLA-4/ VCAM1, and soluble growth factors such as IGF-2. The identification and disruption of signaling pathways that are essential for the survival and expansion of TL blasts has the potential to prevent development of AML in children with Down syndrome by targeted elimination of the preleukemic TL clone. Disclosures: No relevant conflicts of interest to declare.

Suggestion of MUC16 (c.39169C>T) Mutation As a Potential Candidate for Predisposition to Myeloid Malignancy Associated with Trisomy 21

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5094-5094
Author(s):  
Namhee Kim ◽  
Sung-Min Kim ◽  
Si Nae Park ◽  
Kyongok Im ◽  
Jung-Ah Kim ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Down Syndrome ◽  
Trisomy 21 ◽  
Bone Marrow Failure ◽  
Initial Diagnosis ◽  
The Other ◽  
Flow Chart ◽  
Potential Candidate ◽  
Bone Marrow Failure Syndrome ◽  
Gata1 Mutation

Abstract While the majority of leukemia cases occur in the absence of any known predisposing factor, there are germline mutations that significantly increase the risk of developing hematopoietic malignancies in childhood. Germline testing for the predisposition to myeloid malignancies is becoming more common with the recognition of multiple familial syndromes. In USA, Clinical Laboratory Improvement Amendments (CLIA) approved testing exists for mutations in RUNX1, GATA2, CEBPA and the other genes of inherited bone marrow failure syndromes. Meanwhile, GATA1 mutation is almost associated with Down syndrome and in acute myeloid leukemia (AML) with acquired trisomy 21. We experienced a case of infant AML with trisomy 21 and coexisting mutation of MUC16. We experienced infant leukemia (FAB classification, AML M7, Acute megakaryoblasticleukemia) with trisomy 21 and coexisting MUC16, SCRIB, and CEBPA mutation in a 7-month-old boy. Peripheral blood (PB) was taken from the boy every day during hospitalization. Bone marrow (BM) examination was performed at initial diagnosis and after remission. All of PB and BM samples were collected with informed consent, and the study was reviewed and approved by the Institutional Review Board of Seoul National University College of Medicine. The selected five PB samples are demonstrated on Fig. 1. G-banding revealed trisomy 21 and fluorescent in situ hybridization (FISH) for chromosome enumeration 21 revealed 71% with trisomy 21 cells in his diagnosis. At first, we suspected transient abnormal myeloproliferative disease associated with mosaic Down syndrome and serially monitored the proportion of cells with trisomy 21 by FISH and the percentage of blast during hospitalization. Cells with trisomy 21 decreased as blast disappeared in PB during chemotherapy, suggesting trisomy 21 is acquired abnormality in leukemic cells. We performed target gene sequencing of 359 genes related to the hematologic neoplasm, bone marrow failure syndrome, and cancer susceptibility to selected five PB. In addition, to search for the inherited predisposition gene to AML, we also performed whole genome sequencing (WGS) with BM specimen at initial diagnosis and after achieving remission. These next generation sequencing (NGS) with the Illumina HiSeq2500 platform revealed MUC16 (c.39169C>T) is the only significant mutation that persisted throughout from initial diagnosis to post-remission status. Mutations which were seen at initial diagnosis but disappeared after achieving remission were SCRIB (c.2197G>A, p.Arg733Trp) and CEBPA (c.371G>A, p.Ala124Val). To investigate whether MUC16 (c.39169C>T) mutation is rare variant which can be detected in normal person, we screened MUC16 mutation in healthy control (n=365) and in patients with other hematologic diseases (adult myelodysplastic syndrome, n=155; adult aplastic anemia, n=57; adult myeloproliferative neoplasm, n=44; childhood myeloid neoplasm, n=26; inherited bone marrow failure syndrome, n=21; idiopathic eosinophilia, n=4; familiar hemophagocytic lymophohistiocytosis, n=10; congenital neutropenia, n=1) using allele-specific PCR. MUC16 (c.39169C>T) was found in none of them. Discovered site of MUC16 (c.39169C>T) was not reported in solid tumor as well, though the other sites of MUC16 were frequently reported. It is generally known that AML with trisomy 21 accompanies GATA1 mutation, but the infant AML in this study did not accompany GATA1 mutation, but rather, MUC16 mutation. In this patient, GATA1 mutation was not found throughout hospital course. Instead, here we suggest that the constitutional MUC16 (c.39169C>T) mutation coexerts with acquired trisomy 21 in the development of infant AML and that MUC16 (c.39169C>T) mutation is a potential candidate gene for predisposition to AML. Figure 1 Flow chart of PB blasts %, clonal cells % detected by FISH, mutated genes, and the corresponding clinical states. Figure 1. Flow chart of PB blasts %, clonal cells % detected by FISH, mutated genes, and the corresponding clinical states. Disclosures No relevant conflicts of interest to declare.

scholarly journals Characterization of Caenorhabditis elegans Homologs of the Down Syndrome Candidate Gene DYRK1A

Genetics ◽  
2003 ◽  
Vol 163 (2) ◽  
pp. 571-580 ◽  
Author(s):  
William B Raich ◽  
Celine Moorman ◽  
Clay O Lacefield ◽  
Jonah Lehrer ◽  
Dusan Bartsch ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Caenorhabditis Elegans ◽  
Trisomy 21 ◽  
Gene Dosage ◽  
Inducible Promoters ◽  
C Elegans ◽  
Dual Specificity ◽  
Specificity Protein

Abstract The pathology of trisomy 21/Down syndrome includes cognitive and memory deficits. Increased expression of the dual-specificity protein kinase DYRK1A kinase (DYRK1A) appears to play a significant role in the neuropathology of Down syndrome. To shed light on the cellular role of DYRK1A and related genes we identified three DYRK/minibrain-like genes in the genome sequence of Caenorhabditis elegans, termed mbk-1, mbk-2, and hpk-1. We found these genes to be widely expressed and to localize to distinct subcellular compartments. We isolated deletion alleles in all three genes and show that loss of mbk-1, the gene most closely related to DYRK1A, causes no obvious defects, while another gene, mbk-2, is essential for viability. The overexpression of DYRK1A in Down syndrome led us to examine the effects of overexpression of its C. elegans ortholog mbk-1. We found that animals containing additional copies of the mbk-1 gene display behavioral defects in chemotaxis toward volatile chemoattractants and that the extent of these defects correlates with mbk-1 gene dosage. Using tissue-specific and inducible promoters, we show that additional copies of mbk-1 can impair olfaction cell-autonomously in mature, fully differentiated neurons and that this impairment is reversible. Our results suggest that increased gene dosage of human DYRK1A in trisomy 21 may disrupt the function of fully differentiated neurons and that this disruption is reversible.

scholarly journals Identification of novel B-lineage cells in human fetal bone marrow that coexpress CD7 [see comments]

Blood ◽  
1991 ◽  
Vol 77 (1) ◽  
pp. 64-68 ◽  
Author(s):  
ER Grumayer ◽  
F Griesinger ◽  
DS Hummell ◽  
RD Brunning ◽  
JH Kersey
Keyword(s):  
Bone Marrow ◽  
Cell Sorting ◽  
B Cell Development ◽  
Multiparameter Flow Cytometry ◽  
Fetal Bone ◽  
Lymphoid Development ◽  
Alternate Pathway ◽  
Lineage Markers ◽  
B Lineage

Abstract In the present study we used multiparameter flow cytometry and cell sorting to evaluate fetal bone marrow, a rich source of cells early in lymphoid development. We found CD7 to be expressed on a subset of CD19+ cells, including some that had matured to cytoplasmic mu+ (pre-B) and surface mu+ (B) cells. In addition, a less mature CD7+19+ population was characterized as mu- and CD34+/-. The CD7+19+ population was clearly distinct from the mature T cells. The CD7+19+ cells were negative for nuclear TdT in contrast to CD7–19+ cells, which frequently contained TdT. CD10, which is coexpressed on the cell surface of more than 90% of CD19+ lymphocytes, was detected in a minority of CD7+19+ lymphocytes. The CD7+19+34+ cell population may be B-lineage committed, or may represent uncommitted lymphoid precursors. The biologic role of the expression of CD7 on immature and mature cells, including those of the B lineage, may indicate (1) the presence of CD7+19+ lymphoid precursor cells and/or (2) an alternate pathway of B-cell development, in which cells coexpress CD7 with other B-lineage markers.

scholarly journals Molecular Modulation of Fetal Liver Hematopoietic Stem Cell Mobilization into Fetal Bone Marrow in Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Huihong Zeng ◽  
Jiaoqi Cheng ◽  
Ying Fan ◽  
Yingying Luan ◽  
Juan Yang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Vascular Endothelial Cells ◽  
Fetal Liver ◽  
Bone Marrow Niche ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Fetal Bone

Development of hematopoietic stem cells is a complex process, which has been extensively investigated. Hematopoietic stem cells (HSCs) in mouse fetal liver are highly expanded to prepare for mobilization of HSCs into the fetal bone marrow. It is not completely known how the fetal liver niche regulates HSC expansion without loss of self-renewal ability. We reviewed current progress about the effects of fetal liver niche, chemokine, cytokine, and signaling pathways on HSC self-renewal, proliferation, and expansion. We discussed the molecular regulations of fetal HSC expansion in mouse and zebrafish. It is also unknown how HSCs from the fetal liver mobilize, circulate, and reside into the fetal bone marrow niche. We reviewed how extrinsic and intrinsic factors regulate mobilization of fetal liver HSCs into the fetal bone marrow, which provides tools to improve HSC engraftment efficiency during HSC transplantation. Understanding the regulation of fetal liver HSC mobilization into the fetal bone marrow will help us to design proper clinical therapeutic protocol for disease treatment like leukemia during pregnancy. We prospect that fetal cells, including hepatocytes and endothelial and hematopoietic cells, might regulate fetal liver HSC expansion. Components from vascular endothelial cells and bones might also modulate the lodging of fetal liver HSCs into the bone marrow. The current review holds great potential to deeply understand the molecular regulations of HSCs in the fetal liver and bone marrow in mammals, which will be helpful to efficiently expand HSCs in vitro.

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