scholarly journals Lyn kinase promotes erythroblast expansion and late-stage development

Blood ◽  
2006 ◽  
Vol 108 (5) ◽  
pp. 1524-1532 ◽  
Author(s):  
Vinit G. Karur ◽  
Clifford A. Lowell ◽  
Peter Besmer ◽  
Valter Agosti ◽  
Don M. Wojchowski
Keyword(s):  
Late Stage ◽  
Progenitor Cell ◽  
Ex Vivo ◽  
Cell Formation ◽  
Erythroid Cell ◽  
Cycle Phase ◽  
Lyn Kinase ◽  
Death Associated Protein Kinase ◽  
Stage Development ◽  
And Function

Lyn kinase is known to modulate the formation and function of B cells, monocytes, and mast cells. However, Lyn-/- mice also develop erythrosplenomegaly, and cases for both negative and positive erythropoietic actions of Lyn recently have been outlined. In phenylhydrazine-treated Lyn-/- mice, extramedullary splenic erythropoiesis was hyperactivated, but this did not lead to accelerated recovery from anemia. Furthermore, ex vivo analyses of the development of bone marrow-derived Lyn-/- erythroblasts in unique primary culture systems indicated positive roles for Lyn at 2 stages. Late-stage Lyn-/- erythroblasts exhibited deficit Ter119pos cell formation, and this was paralleled by increased apoptosis (and decreased Bcl-xL expression). During early development, Lyn-/- erythroblasts accumulated at a KitposCD71high stage, possessed decreased proliferative capacity, and were attenuated in entering an apparent G1/S cell-cycle phase. In proposed compensatory responses, Lyn-/- erythroblasts expressed increased levels of activated Akt and p60-Src and decreased levels of death-associated protein kinase-2. Stat5 activation and Bcl-xL expression, in contrast, were significantly decreased in keeping with decreased survival and developmental potentials. Lyn, therefore, is proposed to function via erythroid cell-intrinsic mechanisms to promote progenitor cell expansion beyond a KitposCD71high stage and to support subsequent late-stage development.

scholarly journals During EPO or anemia challenge, erythroid progenitor cells transit through a selectively expandable proerythroblast pool

Blood ◽  
2010 ◽  
Vol 116 (24) ◽  
pp. 5334-5346 ◽  
Author(s):  
Arvind Dev ◽  
Jing Fang ◽  
Pradeep Sathyanarayana ◽  
Anamika Pradeep ◽  
Christine Emerson ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Progenitor Cell ◽  
Ex Vivo ◽  
Erythropoietin Receptor ◽  
Erythroid Cell ◽  
Short Term ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells ◽  
Stage Development ◽  
Bcl2 Expression

Abstract Investigations of bone marrow (BM) erythroblast development are important for clinical concerns but are hindered by progenitor cell and tissue availability. We therefore sought to more specifically define dynamics, and key regulators, of the formation of developing BM erythroid cell cohorts. A unique Kit−CD71highTer119− “stage E2” proerythroblast pool first is described, which (unlike its Kit+ “stage E1” progenitors, or maturing Ter119+ “stage E3” progeny) proved to selectively expand ∼ 7-fold on erythropoietin challenge. During short-term BM transplantation, stage E2 proerythroblasts additionally proved to be a predominantly expanded progenitor pool within spleen. This E1→E2→E3 erythroid series reproducibly formed ex vivo, enabling further characterizations. Expansion, in part, involved E1 cell hyperproliferation together with rapid E2 conversion plus E2 stage restricted BCL2 expression. Possible erythropoietin/erythropoietin receptor proerythroblast stage specific events were further investigated in mice expressing minimal erythropoietin receptor alleles. For a hypomorphic erythropoietin receptor-HM allele, major defects in erythroblast development occurred selectively at stage E2. In addition, stage E2 cells proved to interact productively with primary BM stromal cells in ways that enhanced both survival and late-stage development. Overall, findings reveal a novel transitional proerythroblast compartment that deploys unique expansion devices.

scholarly journals Stem cells and lung regeneration

2020 ◽  
Vol 319 (4) ◽  
pp. C675-C693
Author(s):  
Kalpaj R. Parekh ◽  
Janna Nawroth ◽  
Albert Pai ◽  
Shana M. Busch ◽  
Christiana N. Senger ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Lung Disease ◽  
Progenitor Cell ◽  
Human Lung ◽  
Ex Vivo ◽  
Cell Types ◽  
And Function ◽  
Lung Regeneration

The ability to replace defective cells in an airway with cells that can engraft, integrate, and restore a functional epithelium could potentially cure a number of lung diseases. Progress toward the development of strategies to regenerate the adult lung by either in vivo or ex vivo targeting of endogenous stem cells or pluripotent stem cell derivatives is limited by our fundamental lack of understanding of the mechanisms controlling human lung development, the precise identity and function of human lung stem and progenitor cell types, and the genetic and epigenetic control of human lung fate. In this review, we intend to discuss the known stem/progenitor cell populations, their relative differences between rodents and humans, their roles in chronic lung disease, and their therapeutic prospects. Additionally, we highlight the recent breakthroughs that have increased our understanding of these cell types. These advancements include novel lineage-traced animal models and single-cell RNA sequencing of human airway cells, which have provided critical information on the stem cell subtypes, transition states, identifying cell markers, and intricate pathways that commit a stem cell to differentiate or to maintain plasticity. As our capacity to model the human lung evolves, so will our understanding of lung regeneration and our ability to target endogenous stem cells as a therapeutic approach for lung disease.

scholarly journals Attenuation of EPO-dependent erythroblast formation by death-associated protein kinase-2

Blood ◽  
2008 ◽  
Vol 112 (3) ◽  
pp. 886-890 ◽  
Author(s):  
Jing Fang ◽  
Madhu Menon ◽  
Diya Zhang ◽  
Bruce Torbett ◽  
Leif Oxburgh ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Kinase Activity ◽  
Developmental Stages ◽  
Ex Vivo ◽  
Cell Formation ◽  
Transgenic Mouse Model ◽  
Dynamic Modulation ◽  
Stress Erythropoiesis ◽  
Death Associated Protein Kinase ◽  
Apoptotic Factors

Abstract The adult erythron is maintained via dynamic modulation of erythroblast survival potentials. Toward identifying novel regulators of this process, murine splenic erythroblasts at 3 developmental stages were prepared, purified and profiled. Stage-to-stage modulated genes were then functionally categorized, with a focus on apoptotic factors. In parallel with BCL-X and NIX, death-associated protein kinase-2 (DAPK2) was substantially up-modulated during late erythropoiesis. Among hematopoietic lineages, DAPK2 was expressed predominantly in erythroid cells. In a Gata1-IE3.9int-DAPK2 transgenic mouse model, effects on steady-state reticulocyte and red blood cell (RBC) levels were limited. During hemolytic anemia, however, erythropoiesis was markedly deficient. Ex vivo ana-lyses revealed heightened apoptosis due to DAPK2 at a Kit−CD71highTer119− stage, together with a subsequent multifold defect in late-stage Kit−CD71highTer119+ cell formation. In UT7epo cells, siRNA knock-down of DAPK2 enhanced survival due to cytokine withdrawal, and DAPK2's phosphorylation and kinase activity also were erythropoietin (EPO)-modulated. DAPK2 therefore comprises a new candidate attenuator of stress erythropoiesis.

Epo Engages a Tnfr-13c Pathway to Advance for Primary Bone Marrow (Pro)Erythroblast Development

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4238-4238
Author(s):  
Seema Singh ◽  
Arvind Dev ◽  
Pradeep Sathyanarayana ◽  
Donald J McCrann ◽  
Christine Emerson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Late Stage ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Cell Formation ◽  
Erythroid Cell ◽  
Erythroid Progenitors ◽  
Cell Numbers ◽  
Primary Bone ◽  
Primary Bone Marrow

Abstract Abstract 4238 In late stage erythroblasts, EPO can increase levels of Bclx, Bcl2 and/or Mcl1 anti-apoptotic factors. Proerythroblasts, however, are a key EPO target (and exhibit sharp dependence on EPO for growth, and survival). In these progenitors, however, Bclx, Bcl2 and Mcl1 are not prime EPO/EPOR targets. Via transcriptome-based analyses of EPO response circuits in developmentally staged primary bone marrow proerythroblasts (which we now analyze and present at a global level) an atypical TNF receptor, Tnfrsf13c proved to be among the top 1% of EPO/EPOR induced factors. Within lymphoid lineages, Tnfrsf13c is a known receptor for BAFF ligand; and BAFF is an essential mediator of B-cell survival and development. Possible effects of BAFF (a bone marrow stromal cell surface ligand) on primary erythroid cell formation therefore were assessed. Notably, limited BAFF exposure (15 hours) inhibited apoptosis; increased erythroid cell numbers; and enhanced the formation of late-stage Ter119pos erythroblasts. Specifically, cytoprotection by BAFF rivaled that afforded by EPO; cell numbers were enhanced 140% (in 15 hr); and frequencies of Ter119pos erythroblasts were enhanced to 200% of controls. In keeping with Tnfrsf13c's role as an EPOR target, each of the above effects further proved to depend upon proerythroblast exposure to EPO. With regards to Tnfrsf13c expression, analyses using primary erythroid progenitors with knocked-in minimal EPOR alleles indicated dependence for EPO- induction upon JAK2, STAT5 as well as EPOR C-terminal coupled pathways. Studies overall reveal a novel EPOR action route within primary proerythroblasts as a Tnfrsf13c/BAFF pathway (which engages non-canonical NF-kappaB molecular mechanisms). Disclosures: No relevant conflicts of interest to declare.

scholarly journals Plasticity of Cells andEx VivoProduction of Red Blood Cells

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Takashi Hiroyama ◽  
Kenichi Miharada ◽  
Ryo Kurita ◽  
Yukio Nakamura
Keyword(s):  
Red Blood Cells ◽  
Cell Lines ◽  
Blood Cells ◽  
Progenitor Cell ◽  
Ex Vivo ◽  
Es Cells ◽  
Erythroid Cell ◽  
Erythroid Progenitor ◽  
Hematopoietic Stem ◽  
Erythroid Progenitor Cell

The supply of transfusable red blood cells (RBCs) is not sufficient in many countries. If transfusable RBCs could be produced abundantly from certain resources, it would be very useful. Our group has developed a method to produce enucleated RBCs efficiently from hematopoietic stem/progenitor cells present in umbilical cord blood. More recently, it was reported that enucleated RBCs could be abundantly produced from human embryonic stem (ES) cells. The common obstacle for application of these methods is that they require very high cost to produce sufficient number of RBCs that are applicable in the clinic. If erythroid cell lines (immortalized cell lines) able to produce transfusable RBCsex vivowere established, they would be valuable resources. Our group developed a robust method to obtain immortalized erythroid cell lines able to produce mature RBCs. To the best of our knowledge, this was the first paper to show the feasibility of establishing immortalized erythroid progenitor cell lines able to produce enucleated RBCsex vivo. This result strongly suggests that immortalized human erythroid progenitor cell lines able to produce mature RBCsex vivocan also be established.

scholarly journals Cadherins in early neural development

2021 ◽  
Author(s):  
Karolina Punovuori ◽  
Mattias Malaguti ◽  
Sally Lowell
Keyword(s):  
Adhesion Molecules ◽  
Cell Fate ◽  
Neural Development ◽  
Ex Vivo ◽  
Directed Differentiation ◽  
Culture Dish ◽  
Cell Identity ◽  
Cell Fate Decisions ◽  
Neural Tissues ◽  
And Function

AbstractDuring early neural development, changes in signalling inform the expression of transcription factors that in turn instruct changes in cell identity. At the same time, switches in adhesion molecule expression result in cellular rearrangements that define the morphology of the emerging neural tube. It is becoming increasingly clear that these two processes influence each other; adhesion molecules do not simply operate downstream of or in parallel with changes in cell identity but rather actively feed into cell fate decisions. Why are differentiation and adhesion so tightly linked? It is now over 60 years since Conrad Waddington noted the remarkable "Constancy of the Wild Type” (Waddington in Nature 183: 1654–1655, 1959) yet we still do not fully understand the mechanisms that make development so reproducible. Conversely, we do not understand why directed differentiation of cells in a dish is sometimes unpredictable and difficult to control. It has long been suggested that cells make decisions as 'local cooperatives' rather than as individuals (Gurdon in Nature 336: 772–774, 1988; Lander in Cell 144: 955–969, 2011). Given that the cadherin family of adhesion molecules can simultaneously influence morphogenesis and signalling, it is tempting to speculate that they may help coordinate cell fate decisions between neighbouring cells in the embryo to ensure fidelity of patterning, and that the uncoupling of these processes in a culture dish might underlie some of the problems with controlling cell fate decisions ex-vivo. Here we review the expression and function of cadherins during early neural development and discuss how and why they might modulate signalling and differentiation as neural tissues are formed.

271 Investigating the Relationship Between Nursery Pig Performance and Markers of Intestinal Morphology and Integrity

2021 ◽  
Vol 99 (Supplement_1) ◽  
pp. 100-101
Author(s):  
Carson M De Mille ◽  
Nicholas K Gabler
Keyword(s):  
Active Transport ◽  
Feed Intake ◽  
Ex Vivo ◽  
Intestinal Morphology ◽  
Ussing Chambers ◽  
Nursery Pig ◽  
Pig Performance ◽  
Positive Correlations ◽  
And Function ◽  
Time Point

Abstract Weaning induces major structural and function changes to the small intestine of pigs and they transition from milk to solid feedstuffs. Thus, the objective of this study was to determine how intestinal morphology and function markers relate to feed intake and growth rates of nursery pig. Forty-eight weaned pigs (5.63 ± 0.50 kg) were randomly selected, individually penned and fed a common diet. Pig bodyweights and feed intake were determined at d 2, 7, and 21. At each time point, 16 pigs were randomly selected and euthanized. Sections of ileum were assessed for morphology [villus height (VH), crypt depth (CD) and VH:CD] and ex vivo transepithelial resistance (TER), macromolecule permeability (FD4), and active transport of glucose and glutamine via modified Ussing chambers. Within each period (d 0–2, 0–7, and 0–21), Pearson correlations were performed between ADG, ADFI, VH, VH:CD, TER, FD4 and active transport of glucose and glutamine. At d 2 post-weaning, no correlations (P > 0.05) were observed between performance and intestinal variables. By d 7, moderate positive correlations between VH and ADFI (r = 0.69, P = 0.005), VH and ADG (r = 0.68, P = 0.006) were reported. At 21 d post-weaning, moderate positive correlations were still observed for VH and ADFI (r = 0.55, P = 0.026) and between VH and ADG (r = 0.51, P = 0.042). Interestingly, ADFI and ADG tended to be negatively correlated with active glucose transport (r = -0.45, P = 0.083 and r = -0.47, P = 0.064, respectively) and active glutamine transport (r = -0.45, P = 0.083 and r = -0.46, P = 0.073, respectively). Markers of ileal integrity (TER and FD4) were not correlated with ADG or ADFI at any time point. Altogether, these data highlight the importance of intestinal morphology on early nursery pig performance.

268 In-feed Antibiotics Elicit Intestinal Integrity Modifications Early in Post-weaning Life

2021 ◽  
Vol 99 (Supplement_1) ◽  
pp. 99-99
Author(s):  
Jessica M Johnson ◽  
Emma T Helm ◽  
Nicholas K Gabler ◽  
Eric R Burrough ◽  
Carson M De Mille
Keyword(s):  
Growth Performance ◽  
Fixed Effects ◽  
Ex Vivo ◽  
Phase 1 ◽  
Physiological Mechanisms ◽  
Nursery Pigs ◽  
Ussing Chambers ◽  
Intestinal Integrity ◽  
And Function ◽  
Dietary Treatments

Abstract The physiological mechanisms by which in-feed antibiotics improve pig growth performance are largely unknown. One proposed mode of action is improvements in intestinal integrity and function. Therefore, the objective of this study was to test the hypothesis that in-feed therapeutic and sub-therapeutic antibiotics would improve intestinal integrity and function in nursery pigs. Twenty-four weaned pigs (6.1±1.1 kg BW) were randomly allotted to individual pens and assigned one of three dietary treatments as follows (n = 8 pigs/trt): 1) control, no antibiotics (CON), 2) CON + sub-therapeutic chlortetracycline [40 ppm in feed (sCTC)], and 3) CON + chlortetracycline-tiamulin [400 ppm + 35 ppm, respectively (CTCDen)]. The study consisted of two consecutive 14 d phases. Chlortetracycline-tiamulin was only fed in phase 1, sCTC was fed in both phases. Phase 1 and 2 ADG, ADFI, and G:F were determined. After 28 d, ileal and colonic ex vivo intestinal integrity was assessed via transepithelial resistance (TER) and macromolecule flux (FD4) in modified Ussing chambers. All data were analyzed for the fixed effects of treatment and start BW as a covariate. In phase 1, compared with CON and sCTC, CTCDen tended to have greater ADG (0.28, 0.31, and 0.33 kg/d, respectively, P = 0.10) and ADFI (0.28, 0.30, and 0.35 kg/d, respectively, P = 0.09). No differences in phase 1 G:F were observed (P = 0.11). Phase 2 ADG, ADFI, and G:F did not differ (P > 0.10). Further, ileal TER and FD4 did not differ (P > 0.10). Colonic TER tended to be increased in sCTC compared with CON and CTCDen (78, 56, and 59 Ω/cm2, respectively, P = 0.07). Compared with CON, colonic FD4 flux was decreased in sCTC and CTCDen by 35–40% (P = 0.03). Altogether, these data indicate that in-feed antibiotics improve colon integrity early in production which may contribute to improved growth performance.

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