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1.
Cell ; 185(1): 95-112.e18, 2022 01 06.
Article in English | MEDLINE | ID: mdl-34995520

ABSTRACT

Fingerprints are of long-standing practical and cultural interest, but little is known about the mechanisms that underlie their variation. Using genome-wide scans in Han Chinese cohorts, we identified 18 loci associated with fingerprint type across the digits, including a genetic basis for the long-recognized "pattern-block" correlations among the middle three digits. In particular, we identified a variant near EVI1 that alters regulatory activity and established a role for EVI1 in dermatoglyph patterning in mice. Dynamic EVI1 expression during human development supports its role in shaping the limbs and digits, rather than influencing skin patterning directly. Trans-ethnic meta-analysis identified 43 fingerprint-associated loci, with nearby genes being strongly enriched for general limb development pathways. We also found that fingerprint patterns were genetically correlated with hand proportions. Taken together, these findings support the key role of limb development genes in influencing the outcome of fingerprint patterning.


Subject(s)
Dermatoglyphics , Fingers/growth & development , Organogenesis/genetics , Polymorphism, Single Nucleotide , Toes/growth & development , Adolescent , Adult , Aged , Aged, 80 and over , Animals , Asian People/genetics , Body Patterning/genetics , Child , Cohort Studies , Female , Forelimb/growth & development , Genetic Loci , Genome-Wide Association Study , Humans , MDS1 and EVI1 Complex Locus Protein/genetics , Male , Mice , Middle Aged , Young Adult
2.
Development ; 150(23)2023 Dec 01.
Article in English | MEDLINE | ID: mdl-37840454

ABSTRACT

The emergence of definitive human haematopoietic stem cells (HSCs) from Carnegie Stage (CS) 14 to CS17 in the aorta-gonad-mesonephros (AGM) region is a tightly regulated process. Previously, we conducted spatial transcriptomic analysis of the human AGM region at the end of this period (CS16/CS17) and identified secreted factors involved in HSC development. Here, we extend our analysis to investigate the progression of dorso-ventral polarised signalling around the dorsal aorta over the entire period of HSC emergence. Our results reveal a dramatic increase in ventral signalling complexity from the CS13-CS14 transition, coinciding with the first appearance of definitive HSCs. We further observe stage-specific changes in signalling up to CS17, which may underpin the step-wise maturation of HSCs described in the mouse model. The data-rich resource is also presented in an online interface enabling in silico analysis of molecular interactions between spatially defined domains of the AGM region. This resource will be of particular interest for researchers studying mechanisms underlying human HSC development as well as those developing in vitro methods for the generation of clinically relevant HSCs from pluripotent stem cells.


Subject(s)
Hematopoietic Stem Cells , Signal Transduction , Mice , Animals , Humans , Signal Transduction/genetics , Cell Communication , Gene Expression Profiling , Aorta , Mesonephros , Gonads , Hematopoiesis/genetics
3.
Blood ; 136(25): 2893-2904, 2020 12 17.
Article in English | MEDLINE | ID: mdl-32614947

ABSTRACT

Hematopoietic stem and progenitor cells (HSPCs) develop in distinct waves at various anatomical sites during embryonic development. The in vitro differentiation of human pluripotent stem cells (hPSCs) recapitulates some of these processes; however, it has proven difficult to generate functional hematopoietic stem cells (HSCs). To define the dynamics and heterogeneity of HSPCs that can be generated in vitro from hPSCs, we explored single-cell RNA sequencing (scRNAseq) in combination with single-cell protein expression analysis. Bioinformatics analyses and functional validation defined the transcriptomes of naĆÆve progenitors and erythroid-, megakaryocyte-, and leukocyte-committed progenitors, and we identified CD44, CD326, ICAM2/CD9, and CD18, respectively, as markers of these progenitors. Using an artificial neural network that we trained on scRNAseq derived from human fetal liver, we identified a wide range of hPSC-derived HSPCs phenotypes, including a small group classified as HSCs. This transient HSC-like population decreased as differentiation proceeded, and was completely missing in the data set that had been generated using cells selected on the basis of CD43 expression. By comparing the single-cell transcriptome of in vitro-generated HSC-like cells with those generated within the fetal liver, we identified transcription factors and molecular pathways that can be explored in the future to improve the in vitro production of HSCs.


Subject(s)
Antigens, Differentiation , Hematopoietic Stem Cells , Machine Learning , Pluripotent Stem Cells , RNA-Seq , Single-Cell Analysis , Antigens, Differentiation/biosynthesis , Antigens, Differentiation/genetics , Fetus/cytology , Fetus/metabolism , Gene Expression Regulation , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/metabolism , Humans , Liver/cytology , Liver/metabolism , Pluripotent Stem Cells/cytology , Pluripotent Stem Cells/metabolism
4.
Biophys J ; 118(4): 898-908, 2020 02 25.
Article in English | MEDLINE | ID: mdl-31699333

ABSTRACT

Defective nitrate signaling in plants causes disorder in nitrogen metabolism, and it negatively affects nitrate transport systems, which toggle between high- and low-affinity modes in variable soil nitrate conditions. Recent discovery of a plasma membrane nitrate transceptor protein NRT1.1-a transporter cum sensor-provides a clue on this toggling mechanism. However, the general mechanistic description still remains poorly understood. Here, we illustrate adaptive responses and regulation of NRT1.1-mediated nitrate signaling in a wide range of extracellular nitrate concentrations. The results show that the homodimeric structure of NRT1.1 and its dimeric switch play an important role in eliciting specific cytosolic calcium waves sensed by the calcineurin-B-like calcium sensor CBL9, which activates the kinase CIPK23, in low nitrate concentration that is, however, impeded in high nitrate concentration. Nitrate binding at the high-affinity unit initiates NRT1.1 dimer decoupling and priming of the Thr101 site for phosphorylation by CIPK23. This phosphorylation stabilizes the NRT1.1 monomeric state, acting as a high-affinity nitrate transceptor. However, nitrate binding in both monomers, retaining the unmodified NRT1.1 state through dimerization, attenuates CIPK23 activity and thereby maintains the low-affinity mode of nitrate signaling and transport. This phosphorylation-led modulation of NRT1.1 activity shows bistable behavior controlled by an incoherent feedforward loop, which integrates nitrate-induced positive and negative regulatory effects on CIPK23. These results, therefore, advance our molecular understanding of adaptation in fluctuating nutrient availability and are a way forward for improving plant nitrogen use efficiency.


Subject(s)
Arabidopsis , Nitrates , Anion Transport Proteins , Arabidopsis/metabolism , Nitrate Transporters , Nitrates/metabolism , Plant Proteins/metabolism
5.
Development ; 144(13): 2323-2337, 2017 07 01.
Article in English | MEDLINE | ID: mdl-28676567

ABSTRACT

Haematopoietic stem cells (HSCs) emerge during embryogenesis and give rise to the adult haematopoietic system. Understanding how early haematopoietic development occurs is of fundamental importance for basic biology and medical sciences, but our knowledge is still limited compared with what we know of adult HSCs and their microenvironment. This is particularly true for human haematopoiesis, and is reflected in our current inability to recapitulate the development of HSCs from pluripotent stem cells in vitro In this Review, we discuss what is known of human haematopoietic development: the anatomical sites at which it occurs, the different temporal waves of haematopoiesis, the emergence of the first HSCs and the signalling landscape of the haematopoietic niche. We also discuss the extent to which in vitro differentiation of human pluripotent stem cells recapitulates bona fide human developmental haematopoiesis, and outline some future directions in the field.


Subject(s)
Embryo Culture Techniques/methods , Embryo, Mammalian/cytology , Hematopoietic Stem Cells/cytology , Hematopoiesis , Humans , Phenotype , Regeneration
6.
Development ; 143(8): 1284-9, 2016 Apr 15.
Article in English | MEDLINE | ID: mdl-27095492

ABSTRACT

One day prior to mass emergence of haematopoietic stem cells (HSCs) in the foetal liver at E12.5, the embryo contains only a few definitive HSCs. It is thought that the burst of HSC activity in the foetal liver is underpinned by rapid maturation of immature embryonic precursors of definitive HSCs, termed pre-HSCs. However, because pre-HSCs are not detectable by direct transplantations into adult irradiated recipients, the size and growth of this population, which represents the embryonic rudiment of the adult haematopoietic system, remains uncertain. Using a novel quantitative assay, we demonstrate that from E9.5 the pre-HSC pool undergoes dramatic growth in the aorta-gonad-mesonephros region and by E11.5 reaches the size that matches the number of definitive HSCs in the E12.5 foetal liver. Thus, this study provides for the first time a quantitative basis for our understanding of how the large population of definitive HSCs emerges in the foetal liver.


Subject(s)
Cell Differentiation , Hematopoietic Stem Cells/cytology , Liver/embryology , Animals , Cell Count , Cell Proliferation , Cells, Cultured , Liver/cytology , Mice , Mice, Inbred C57BL , Time Factors
7.
J Am Soc Nephrol ; 29(7): 1859-1873, 2018 07.
Article in English | MEDLINE | ID: mdl-29777019

ABSTRACT

Background Interstitial fibrosis is associated with chronic renal failure. In addition to fibroblasts, bone marrow-derived cells and tubular epithelial cells have the capacity to produce collagen. However, the amount of collagen produced by each of these cell types and the relevance of fibrosis to renal function are unclear.Methods We generated conditional cell type-specific collagen I knockout mice and used (reversible) unilateral ureteral obstruction and adenine-induced nephropathy to study renal fibrosis and function.Results In these mouse models, hematopoietic, bone marrow-derived cells contributed to 38%-50% of the overall deposition of collagen I in the kidney. The influence of fibrosis on renal function was dependent on the type of damage. In unilateral ureteral obstruction, collagen production by resident fibroblasts was essential to preserve renal function, whereas in the chronic model of adenine-induced nephropathy, collagen production was detrimental to renal function.Conclusions Our data show that hematopoietic cells are a major source of collagen and that antifibrotic therapies need to be carefully considered depending on the type of disease and the underlying cause of fibrosis.


Subject(s)
Acute Kidney Injury/metabolism , Collagen Type I/genetics , Collagen Type I/metabolism , Kidney/pathology , Renal Insufficiency, Chronic/metabolism , Acute Kidney Injury/etiology , Acute Kidney Injury/pathology , Acute Kidney Injury/physiopathology , Adenine , Animals , Bone Marrow Cells/metabolism , Cell Lineage , Epithelial Cells/metabolism , Female , Fibroblasts/metabolism , Fibrosis , Glomerular Filtration Rate , Hematopoiesis , Kidney/physiopathology , Kidney Tubules/cytology , Mice , Mice, Knockout , Renal Insufficiency, Chronic/chemically induced , Renal Insufficiency, Chronic/pathology , Renal Insufficiency, Chronic/physiopathology , Ureteral Obstruction/complications
8.
Development ; 142(1): 17-20, 2015 Jan 01.
Article in English | MEDLINE | ID: mdl-25516966

ABSTRACT

In September 2014, over 100 scientists from around the globe gathered at Wotton House near London for the Company of Biologists' workshop 'From Stem Cells to Human Development'. The workshop covered diverse aspects of human development, from the earliest stages of embryogenesis to differentiation of mature cell types of all three germ layers from pluripotent cells. In this Meeting Review, we summarise some of the exciting data presented at the workshop and draw together the main themes that emerged.


Subject(s)
Embryonic Development , Stem Cells/cytology , Animals , Disease , Embryo Implantation , Health , Hematopoiesis , Humans , Mice , Organogenesis , Pluripotent Stem Cells/cytology
9.
Blood ; 127(15): 1907-11, 2016 Apr 14.
Article in English | MEDLINE | ID: mdl-26773036

ABSTRACT

Since its discovery in the late 1990s, Pten has turned out to be one of the most important tumor suppressor genes. Pten loss results in increased activation of the phosphatidylinositol 3-kinase/Akt signaling pathway, which is associated with increased proliferation, survival, and neoplastic growth. Here, we have addressed the effects of conditional deletion of Pten in hematopoietic cells by crossing Pten conditional knockout mice with a knock-in mouse expressing the Cre recombinase in the CD45 locus. CD45 is also known as leukocyte common antigen, and it is expressed in virtually all white cells and in hematopoietic stem cells. Using a reporter mouse, we demonstrate that CD45:Cre mouse displays recombinase activity in both myeloid and lymphoid cells. However, deletion of Pten in CD45-expressing cells induces development of T-cell acute lymphoblastic leukemia and lymphoma, but not other hematologic malignancies.


Subject(s)
Leukocyte Common Antigens/metabolism , Myeloproliferative Disorders/genetics , Myeloproliferative Disorders/metabolism , PTEN Phosphohydrolase/metabolism , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Animals , Bone Marrow Cells/metabolism , Disease Models, Animal , Female , Flow Cytometry , Gene Deletion , Hematopoietic Stem Cells/cytology , Integrases/metabolism , Kaplan-Meier Estimate , Male , Mice , Mice, Knockout
10.
Blood ; 128(12): 1567-77, 2016 09 22.
Article in English | MEDLINE | ID: mdl-27421959

ABSTRACT

The first definitive hematopoietic stem cells (dHSCs) in the mouse emerge in the dorsal aorta of the embryonic day (E) 10.5 to 11 aorta-gonad-mesonephros (AGM) region. Notch signaling is essential for early HSC development but is dispensable for the maintenance of adult bone marrow HSCs. How Notch signaling regulates HSC formation in the embryo is poorly understood. We demonstrate here that Notch signaling is active in E10.5 HSC precursors and involves both Notch1 and Notch2 receptors, but is gradually downregulated while they progress toward dHSCs at E11.5. This downregulation is accompanied by gradual functional loss of Notch dependency. Thus, as early as at final steps in the AGM region, HSCs begin acquiring the Notch independency characteristic of adult bone marrow HSCs as part of the maturation program. Our data indicate that fine stage-dependent tuning of Notch signaling may be required for the generation of definitive HSCs from pluripotent cells.


Subject(s)
Aorta/embryology , Embryo, Mammalian/cytology , Gonads/embryology , Hematopoietic Stem Cells/cytology , Mesonephros/embryology , Receptor, Notch2/metabolism , Stromal Cells/cytology , Animals , Aorta/metabolism , Cells, Cultured , Embryo, Mammalian/metabolism , Gonads/metabolism , Hematopoietic Stem Cell Transplantation , Hematopoietic Stem Cells/metabolism , Mesonephros/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Signal Transduction , Stromal Cells/metabolism
11.
Development ; 141(17): 3319-23, 2014 Sep.
Article in English | MEDLINE | ID: mdl-25139854

ABSTRACT

Haematopoiesis in adult animals is maintained by haematopoietic stem cells (HSCs), which self-renew and can give rise to all blood cell lineages. The AGM region is an important intra-embryonic site of HSC development and a wealth of evidence indicates that HSCs emerge from the endothelium of the embryonic dorsal aorta and extra-embryonic large arteries. This, however, is a stepwise process that occurs through sequential upregulation of CD41 and CD45 followed by emergence of fully functional definitive HSCs. Although largely dispensable at later stages, the Runx1 transcription factor is crucially important during developmental maturation of HSCs; however, exact points of crucial involvement of Runx1 in this multi-step developmental maturation process remain unclear. Here, we have investigated requirements for Runx1 using a conditional reversible knockout strategy. We report that Runx1 deficiency does not preclude formation of VE-cad+CD45-CD41+ cells, which are phenotypically equivalent to precursors of definitive HSCs (pre-HSC Type I) but blocks transition to the subsequent CD45+ stage (pre-HSC Type II). These data emphasise that developmental progression of HSCs during a very short period of time is regulated by precise stage-specific molecular mechanisms.


Subject(s)
Cell Lineage , Core Binding Factor Alpha 2 Subunit/metabolism , Embryo, Mammalian/cytology , Hematopoietic Stem Cells/cytology , Platelet Membrane Glycoprotein IIb/metabolism , Animals , Core Binding Factor Alpha 2 Subunit/deficiency , Hematopoietic Stem Cells/metabolism , Integrases/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout
12.
Blood ; 124(17): 2725-9, 2014 Oct 23.
Article in English | MEDLINE | ID: mdl-25079356

ABSTRACT

In this study, we test the assumption that the hematopoietic progenitor/colony-forming cells of the embryonic yolk sac (YS), which are endowed with megakaryocytic potential, differentiate into the first platelet-forming cells in vivo. We demonstrate that from embryonic day (E) 8.5 all megakaryocyte (MK) colony-forming cells belong to the conventional hematopoietic progenitor cell (HPC) compartment. Although these cells are indeed capable of generating polyploid MKs, they are not the source of the first platelet-forming cells. We show that proplatelet formation first occurs in a unique and previously unrecognized lineage of diploid platelet-forming cells, which develop within the YS in parallel to HPCs but can be specified in the E8.5 Runx1-null embryo despite the absence of the progenitor cell lineage.


Subject(s)
Cell Lineage/genetics , Diploidy , Embryo, Mammalian/metabolism , Megakaryocyte Progenitor Cells/metabolism , Megakaryocytes/metabolism , Polyploidy , Animals , Core Binding Factor Alpha 2 Subunit/genetics , Core Binding Factor Alpha 2 Subunit/metabolism , Embryo, Mammalian/cytology , Embryo, Mammalian/embryology , Gene Expression Regulation, Developmental , Megakaryocyte Progenitor Cells/cytology , Megakaryocytes/cytology , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Microscopy, Confocal , Oligonucleotide Array Sequence Analysis , Time Factors , Transcriptome , Yolk Sac/cytology , Yolk Sac/embryology , Yolk Sac/metabolism
13.
Exp Cell Res ; 332(2): 163-78, 2015 Mar 15.
Article in English | MEDLINE | ID: mdl-25645944

ABSTRACT

The indifferent mammalian embryonic gonad generates an ovary or testis, but the factors involved are still poorly known. The Wnt-4 signal represents one critical female determinant, since its absence leads to partial female-to-male sex reversal in mouse, but its signalling is as well implicated in the testis development. We used the Wnt-4 deficient mouse as a model to identify candidate gonadogenesis genes, and found that the Notum, Phlda2, Runx-1 and Msx1 genes are typical of the wild-type ovary and the Osr2, Dach2, Pitx2 and Tacr3 genes of the testis. Strikingly, the expression of these latter genes becomes reversed in the Wnt-4 knock-out ovary, suggesting a role in ovarian development. We identified the transcription factor Runx-1 as a Wnt-4 signalling target gene, since it is expressed in the ovary and is reduced upon Wnt-4 knock-out. Consistent with this, introduction of the Wnt-4 signal into early ovary cells ex vivo induces Runx-1 expression, while conversely Wnt-4 expression is down-regulated in the absence of Runx-1. We conclude that the Runx-1 gene can be a Wnt-4 signalling target, and that Runx-1 and Wnt-4 are mutually interdependent in their expression. The changes in gene expression due to the absence of Wnt-4 in gonads reflect the sexually dimorphic role of this signal and its complex gene network in mammalian gonad development.


Subject(s)
Gene Expression Regulation, Developmental , Ovary/metabolism , Wnt4 Protein/physiology , Animals , Base Sequence , Binding Sites , Cells, Cultured , Core Binding Factor Alpha 2 Subunit/genetics , Core Binding Factor Alpha 2 Subunit/metabolism , Female , Gene Expression , Male , Mice, Knockout , Ovary/embryology , Sex Determination Processes/genetics , Tissue Culture Techniques , Wnt Signaling Pathway
14.
BMC Dev Biol ; 15: 35, 2015 Oct 09.
Article in English | MEDLINE | ID: mdl-26453549

ABSTRACT

BACKGROUND: Pluripotent cells are present in early embryos until the levels of the pluripotency regulator Oct4 drop at the beginning of somitogenesis. Elevating Oct4 levels in explanted post-pluripotent cells in vitro restores their pluripotency. Cultured pluripotent cells can participate in normal development when introduced into host embryos up to the end of gastrulation. In contrast, pluripotent cells efficiently seed malignant teratocarcinomas in adult animals. In humans, extragonadal teratomas and teratocarcinomas are most frequently found in the sacrococcygeal region of neonates, suggesting that these tumours originate from cells in the posterior of the embryo that either reactivate or fail to switch off their pluripotent status. However, experimental models for the persistence or reactivation of pluripotency during embryonic development are lacking. METHODS: We manually injected embryonic stem cells into conceptuses at E9.5 to test whether the presence of pluripotent cells at this stage correlates with teratocarcinoma formation. We then examined the effects of reactivating embryonic Oct4 expression ubiquitously or in combination with Nanog within the primitive streak (PS)/tail bud (TB) using a transgenic mouse line and embryo chimeras carrying a PS/TB-specific heterologous gene expression cassette respectively. RESULTS: Here, we show that pluripotent cells seed teratomas in post-gastrulation embryos. However, at these stages, induced ubiquitous expression of Oct4 does not lead to restoration of pluripotency (indicated by Nanog expression) and tumour formation in utero, but instead causes a severe phenotype in the extending anteroposterior axis. Use of a more restricted T(Bra) promoter transgenic system enabling inducible ectopic expression of Oct4 and Nanog specifically in the posteriorly-located primitive streak (PS) and tail bud (TB) led to similar axial malformations to those induced by Oct4 alone. These cells underwent induction of pluripotency marker expression in Epiblast Stem Cell (EpiSC) explants derived from somitogenesis-stage embryos, but no teratocarcinoma formation was observed in vivo. CONCLUSIONS: Our findings show that although pluripotent cells with teratocarcinogenic potential can be produced in vitro by the overexpression of pluripotency regulators in explanted somitogenesis-stage somatic cells, the in vivo induction of these genes does not yield tumours. This suggests a restrictive regulatory role of the embryonic microenvironment in the induction of pluripotency.


Subject(s)
Embryo, Mammalian/metabolism , Embryonic Stem Cells/metabolism , Teratoma/metabolism , Teratoma/pathology , Animals , Embryo, Mammalian/pathology , Fetal Proteins/metabolism , Homeodomain Proteins/genetics , Humans , Mice , Nanog Homeobox Protein , Octamer Transcription Factor-3/genetics , Octamer Transcription Factor-3/metabolism , Pluripotent Stem Cells/metabolism , T-Box Domain Proteins/metabolism , Tail/embryology
15.
Blood ; 122(14): 2338-45, 2013 Oct 03.
Article in English | MEDLINE | ID: mdl-23863896

ABSTRACT

During mouse development, definitive hematopoietic stem cells (dHSCs) emerge by late E10.5 to E11 in several hematopoietic sites. Of them, the aorta-gonad-mesonephros (AGM) region drew particular attention owing to its capacity to autonomously initiate and expand dHSCs in culture, indicating its key role in HSC development. The dorsal aorta contains characteristic hematopoietic clusters and is the initial site of dHSC emergence, where they mature through vascular endothelial (VE)-cadherin(+)CD45(-)CD41(low) (type 1 pre-HSCs) and VE-cadherin(+)CD45(+) (type 2 pre-HSCs) intermediates. Although dHSCs were also found in other embryonic niches (placenta, yolk sac, and extraembryonic vessels), attempts to detect their HSC initiating potential have been unsuccessful to date. Extraembryonic arterial vessels contain hematopoietic clusters, suggesting that they develop HSCs, but functional evidence for this has been lacking. Here we show that umbilical cord and vitelline arteries (VAs), but not veins, contain pre-HSCs capable of maturing into dHSCs in the presence of exogenous interleukin 3, although in fewer numbers than the AGM region, and that pre-HSC activity in VAs increases with proximity to the embryo proper. Our functional data strongly suggest that extraembryonic arteries can actively contribute to adult hematopoiesis.


Subject(s)
Hematopoiesis/physiology , Hematopoietic Stem Cells/cytology , Umbilical Arteries/cytology , Vitelline Duct/cytology , Animals , Flow Cytometry , Mice , Mice, Inbred C57BL , Reverse Transcriptase Polymerase Chain Reaction , Umbilical Arteries/embryology , Vitelline Duct/blood supply , Vitelline Duct/embryology
16.
Development ; 138(6): 1017-31, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21343360

ABSTRACT

Definitive hematopoietic stem cells (HSCs) lie at the foundation of the adult hematopoietic system and provide an organism throughout its life with all blood cell types. Several tissues demonstrate hematopoietic activity at early stages of embryonic development, but which tissue is the primary source of these important cells and what are the early embryonic ancestors of definitive HSCs? Here, we review recent advances in the field of HSC research that have shed light on such questions, while setting them into a historical context, and discuss key issues currently circulating in this field.


Subject(s)
Embryonic Development/physiology , Hematopoietic Stem Cells/physiology , Hematopoietic System/embryology , Adult , Animals , Embryo Research , Embryo, Mammalian , Hematopoiesis/physiology , Humans , Models, Biological
17.
Blood ; 117(13): 3521-8, 2011 Mar 31.
Article in English | MEDLINE | ID: mdl-21278354

ABSTRACT

Hoxb4 overexpression promotes dramatic expansion of bone marrow (BM) hematopoietic stem cells (HSCs) without leukemic transformation and induces development of definitive HSCs from early embryonic yolk sac and differentiating embryonic stem cells. Knockout studies of Hoxb4 showed little effect on hematopoiesis, but interpretation of these results is obscured by the lack of direct evidence that Hoxb4 is expressed in HSCs and possible compensatory effects of other (Hox) genes. To evaluate accurately the pattern of Hoxb4 expression and to gain a better understanding of the physiologic role of Hoxb4 in the hemato-poietic system, we generated a knock-in Hoxb4-yellow fluorescent protein (YFP) reporter mouse model. We show that BM Lin(-)Sca1(+)c-Kit(+) cells express Hoxb4-YFP and demonstrate functionally in the long-term repopulation assay that definitive HSCs express Hoxb4. Similarly, aorta-gonad-mesonephrous-derived CD45(+)CD144(+) cells, enriched for HSCs, express Hoxb4. Furthermore, yolk sac and placental HSC populations express Hoxb4. Unexpectedly, Hoxb4 expression in the fetal liver HSCs is lower than in the BM, reaching negligible levels in some HSCs, suggesting an insignificant role of Hoxb4 in expansion of fetal liver HSCs. Hoxb4 expression therefore would not appear to correlate with the cycling status of fetal liver HSCs, although highly proliferative HSCs from young BM show strong Hoxb4 expression.


Subject(s)
Bacterial Proteins/genetics , Cell Tracking/methods , Genes, Reporter , Hematopoiesis/genetics , Hematopoietic Stem Cells/physiology , Homeodomain Proteins/genetics , Homeodomain Proteins/physiology , Luminescent Proteins/genetics , Transcription Factors/genetics , Transcription Factors/physiology , Animals , Bacterial Proteins/metabolism , Embryo, Mammalian , Female , Genes, Reporter/physiology , Hematopoiesis/physiology , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/metabolism , Homeodomain Proteins/metabolism , Luminescent Proteins/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Models, Animal , Models, Biological , Pregnancy , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Transcription Factors/metabolism
18.
Sci Rep ; 13(1): 10124, 2023 06 22.
Article in English | MEDLINE | ID: mdl-37349488

ABSTRACT

We present an approach (knowledge-and-data-driven, KDD, modeling) that allows us to get closer to understanding the processes that affect the dynamics of plankton communities. This approach, based on the use of time series obtained as a result of ecosystem monitoring, combines the key features of both the knowledge-driven modeling (mechanistic models) and data-driven (DD) modeling. Using a KDD model, we reveal the phytoplankton growth-rate fluctuations in the ecosystem of the Naroch Lakes and determine the degree of phase synchronization between fluctuations in the phytoplankton growth rate and temperature variations. More specifically, we estimate a numerical value of the phase locking index (PLI), which allows us to assess how temperature fluctuations affect the dynamics of phytoplankton growth rates. Since, within the framework of KDD modeling, we directly include the time series obtained as a result of field measurements in the model equations, the dynamics of the phytoplankton growth rate obtained from the KDD model reflect the behavior of the lake ecosystem as a whole, and PLI can be considered as a holistic parameter.


Subject(s)
Ecosystem , Phytoplankton , Phytoplankton/physiology , Temperature , Plankton/physiology , Lakes
19.
Sci Transl Med ; 15(698): eabn0736, 2023 05 31.
Article in English | MEDLINE | ID: mdl-37256934

ABSTRACT

Progressive fibrosis is a feature of aging and chronic tissue injury in multiple organs, including the kidney and heart. Glioma-associated oncogene 1 expressing (Gli1+) cells are a major source of activated fibroblasts in multiple organs, but the links between injury, inflammation, and Gli1+ cell expansion and tissue fibrosis remain incompletely understood. We demonstrated that leukocyte-derived tumor necrosis factor (TNF) promoted Gli1+ cell proliferation and cardiorenal fibrosis through induction and release of Indian Hedgehog (IHH) from renal epithelial cells. Using single-cell-resolution transcriptomic analysis, we identified an "inflammatory" proximal tubular epithelial (iPT) population contributing to TNF- and nuclear factor κB (NF-κB)-induced IHH production in vivo. TNF-induced Ubiquitin D (Ubd) expression was observed in human proximal tubular cells in vitro and during murine and human renal disease and aging. Studies using pharmacological and conditional genetic ablation of TNF-induced IHH signaling revealed that IHH activated canonical Hedgehog signaling in Gli1+ cells, which led to their activation, proliferation, and fibrosis within the injured and aging kidney and heart. These changes were inhibited in mice by Ihh deletion in Pax8-expressing cells or by pharmacological blockade of TNF, NF-κB, or Gli1 signaling. Increased amounts of circulating IHH were associated with loss of renal function and higher rates of cardiovascular disease in patients with chronic kidney disease. Thus, IHH connects leukocyte activation to Gli1+ cell expansion and represents a potential target for therapies to inhibit inflammation-induced fibrosis.


Subject(s)
Hedgehog Proteins , Renal Insufficiency, Chronic , Animals , Humans , Mice , Fibrosis , Hedgehog Proteins/metabolism , Inflammation , NF-kappa B , Tumor Necrosis Factors , Zinc Finger Protein GLI1
20.
BMC Biol ; 9: 88, 2011 Dec 28.
Article in English | MEDLINE | ID: mdl-22204560

ABSTRACT

The close association between hematopoietic and endothelial cells during embryonic development led to the proposal that they may originate from a common ancestor--the hemangioblast. Due to a lack of unique specific markers for in vivo cell fate tracking studies, evidence supporting this theory derives mainly from in vitro differentiation studies. Teixeira and colleagues describe a novel enhancer that drives specific eGFP expression in blood islands of the electroporated chick embryo, thereby presenting a tool potentially suitable for analysis of hemangioblast differentiation and development of blood islands.


Subject(s)
Endothelial Cells/cytology , Hematopoietic Stem Cells/cytology , Animals , Cell Differentiation , Chick Embryo , Electroporation , Hematopoiesis
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