scholarly journals A single wave of monocytes is sufficient to replenish the long-term Langerhans cell network after immune injury

2019 ◽  
Author(s):  
Ivana R. Ferrer ◽  
Heather C. West ◽  
Stephen Henderson ◽  
Dmitry S. Ushakov ◽  
Pedro Santos e Sousa ◽  
...  
Keyword(s):  
Langerhans Cells ◽  
Ultra Violet ◽  
Functional Adaptation ◽  
List Type ◽  
Single Wave ◽  
Hematopoietic Stem ◽  
Cell Network ◽  
Immune Injury ◽  
Turn Over

Abstract Embryo-derived Langerhans cells (eLC) are maintained within the sealed epidermis without contribution from circulating cells. When the network is perturbed by transient exposure to ultra-violet light, short-term LC are temporarily reconstituted from an initial wave of monocytes, but thought to be superseded by more permanent repopulation with undefined LC precursors. However, the extent to which this mechanism is relevant to immune-pathological processes that damage LC population integrity is not known. Using a model of allogeneic hematopoietic stem cell transplantation, where allo-reactive T cells directly target eLC, we have asked if and how the original LC network is ultimately restored. We find that donor monocytes, but not dendritic cells, are the precursors of the long-term LC in this context. Destruction of eLC leads to recruitment of a single wave of monocytes which engraft in the epidermis and undergo a sequential pathway of differentiation via transcriptionally distinct EpCAM+ precursors. Monocyte-derived LC acquire the capacity of self-renewal, and turn-over in the epidermis was remarkably similar to that of steady state eLC. However, we have identified a bottleneck in the differentiation and survival of epidermal monocytes, which together with the slow turn-over of mature LC limits repair of the network. Furthermore, replenishment of the LC network leads to constitutive entry of cells into the epidermal compartment. Thus, immune injury triggers functional adaptation of mechanisms used to maintain tissue-resident macrophages at other sites, but this process is highly inefficient in the skin. Highlights Immune injury leads to recruitment of a single wave of monocytes to replace resident Langerhans cells (LC). DC lineage cells cannot become long-term replacement LC. The size of the re-emerging network is controlled by density-dependent division of mature LC. Immune injury and inefficient repopulation by monocyte-derived cells lead to a permanently altered LC niche.

scholarly journals A wave of monocytes is recruited to replenish the long-term Langerhans cell network after immune injury

2019 ◽  
Vol 4 (38) ◽  
pp. eaax8704 ◽  
Author(s):  
Ivana R. Ferrer ◽  
Heather C. West ◽  
Stephen Henderson ◽  
Dmitry S. Ushakov ◽  
Pedro Santos e Sousa ◽  
...  
Keyword(s):  
Functional Adaptation ◽  
Dense Population ◽  
Short Term ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Cell Network ◽  
Circulating Cells ◽  
Initial Wave ◽  
Immune Injury

A dense population of embryo-derived Langerhans cells (eLCs) is maintained within the sealed epidermis without contribution from circulating cells. When this network is perturbed by transient exposure to ultraviolet light, short-term LCs are temporarily reconstituted from an initial wave of monocytes but thought to be superseded by more permanent repopulation with undefined LC precursors. However, the extent to which this process is relevant to immunopathological processes that damage LC population integrity is not known. Using a model of allogeneic hematopoietic stem cell transplantation, where alloreactive T cells directly target eLCs, we have asked whether and how the original LC network is ultimately restored. We find that donor monocytes, but not dendritic cells, are the precursors of long-term LCs in this context. Destruction of eLCs leads to recruitment of a wave of monocytes that engraft in the epidermis and undergo a sequential pathway of differentiation via transcriptionally distinct EpCAM+precursors. Monocyte-derived LCs acquire the capacity of self-renewal, and proliferation in the epidermis matched that of steady-state eLCs. However, we identified a bottleneck in the differentiation and survival of epidermal monocytes, which, together with the slow rate of renewal of mature LCs, limits repair of the network. Furthermore, replenishment of the LC network leads to constitutive entry of cells into the epidermal compartment. Thus, immune injury triggers functional adaptation of mechanisms used to maintain tissue-resident macrophages at other sites, but this process is highly inefficient in the skin.

scholarly journals Modulation of Aplnr signaling is required during the development and maintenance of the hematopoietic system

2020 ◽  
Author(s):  
Melany Jackson ◽  
Antonella Fidanza ◽  
A. Helen Taylor ◽  
Stanislav Rybtsov ◽  
Richard Axton ◽  
...  
Keyword(s):  
Stem Cells ◽  
Ex Vivo ◽  
Embryonic Stem ◽  
Mouse Embryonic Stem Cell ◽  
Null Mouse ◽  
List Type ◽  
Hematopoietic Stem ◽  
Apelin Receptor

ABSTRACTApelin receptor (Aplnr/Agtrl1/Apj) marks a transient cell population during the differentiation of hematopoietic progenitor cells (HPCs) from pluripotent stem cells but the function of this signalling pathway during hematopoietic development both in vitro and in vitro is poorly understood. We generated an Aplnr-null mouse embryonic stem cell (mESC) line and demonstrated that they are significantly impaired in the production of HPCs indicating that the Aplnr pathway is required for their formation. Using Aplnr-tdTomato reporter mESCs we demonstrated that is expressed in a population of differentiating mesodermal cells committed to a hematopoietic and endothelial fate. Activation of this signaling pathway by the addition of the Apelin ligand to differentiating ESCs has no effect on the production of HPCs but the addition to ex vivo AGM cultures impaired the generation of long term reconstituting hematopoietic stem cells and appeared to drive myeloid differentiation. Taken together, our data suggest that the Aplnr pathway is required for the generation of cells that give rise to HSCs during development but its subsequent down regulation is required for their maintenance.HIGHLIGHTSHematopoietic differentiation is impaired in Aplnr-null ESCsAplnr-tdTomato reporter marks a subpopulation of ESC-derived mesoderm.Aplnr signaling drives the maturation of lineage-committed myeloid progenitorsIn AGM explant cultures HSC activity is reduced in the presence of Aplnr ligands.

Strategies to Protect Hematopoietic Stem Cells from Culture-Induced Stress Conditions

2020 ◽  
Vol 15 ◽  
Author(s):  
Fatima Aerts-Kaya
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Ex Vivo ◽  
Stress Conditions ◽  
Stress Factors ◽  
Hematopoietic Stem ◽  
Induced Stress

: In contrast to their almost unlimited potential for expansion in vivo and despite years of dedicated research and optimization of expansion protocols, the expansion of Hematopoietic Stem Cells (HSCs) in vitro remains remarkably limited. Increased understanding of the mechanisms that are involved in maintenance, expansion and differentiation of HSCs will enable the development of better protocols for expansion of HSCs. This will allow procurement of HSCs with long-term engraftment potential and a better understanding of the effects of the external influences in and on the hematopoietic niche that may affect HSC function. During collection and culture of HSCs, the cells are exposed to suboptimal conditions that may induce different levels of stress and ultimately affect their self-renewal, differentiation and long-term engraftment potential. Some of these stress factors include normoxia, oxidative stress, extra-physiologic oxygen shock/stress (EPHOSS), endoplasmic reticulum (ER) stress, replicative stress, and stress related to DNA damage. Coping with these stress factors may help reduce the negative effects of cell culture on HSC potential, provide a better understanding of the true impact of certain treatments in the absence of confounding stress factors. This may facilitate the development of better ex vivo expansion protocols of HSCs with long-term engraftment potential without induction of stem cell exhaustion by cellular senescence or loss of cell viability. This review summarizes some of available strategies that may be used to protect HSCs from culture-induced stress conditions.

scholarly journals P044 Can an electronic prescribing system ensure clear anticoagulation discharge communication?

2019 ◽  
Vol 104 (7) ◽  
pp. e2.49-e2
Author(s):  
Susie Gage
Keyword(s):  
Patient Safety ◽  
Discharge Summary ◽  
Electronic Prescribing ◽  
List Type ◽  
Heparin Infusion ◽  
National Patient Safety Agency ◽  
High Dependency ◽  
National Patient ◽  
Discharge Summaries

AimThe National Patient Safety Agency (NPSA)1 identified heparin as a major cause of adverse events associated with adverse incidents, including some fatalities. By ensuring good communication, this should be associated with risk reduction.1 The aim of this study was to ensure there is clear anticoagulation communication on discharge, from the paediatric intensive care unit (PICU) electronic prescribing system (Philips), to the paediatric cardiac high dependency unit and paediatric cardiac ward. To investigate whether the heparin regimen complies with the hospital’s anticoagulant guidelines and if there is any deviation; that this is clearly documented. To find out if there is an indication documented for the heparin regimen chosen and if there is a clear long term plan documented for the patient, after heparin cessation.MethodsA report was generated for all patients who were prescribed a heparin infusion on PICU, between 1st January 2018 and 30th June 2018, from the Philips system. All discharge summaries from the PICU Philips system were reviewed. Only paediatric cardiac patients were included that had a heparin infusion prescribed on discharge, all other discharge summaries were excluded from the study. Each discharge summary was reviewed in the anticoagulant section; for the heparin regimen chosen, whether it complies with the hospital’s anticoagulant guidelines and if there was any deviation whether this was documented. The indication documented of which heparin regimen was chosen and whether a clear long term plan was documented after heparin cessation; for example if the patient is to be transferred onto aspirin, clopidogrel, warfarin or enoxaparin.Results82 discharge summaries were reviewed over the 6 month period between 1st January 2018 and 30th June 2018; 16 were excluded as were not paediatric cardiac, leaving 66 paediatric cardiac discharge summaries that were reviewed. 45 out of 66 (68%) complied with the hospital’s heparin anticoagulation guidelines. Of the 32% that deviated from the protocol; only 33% (7 out of 21) had a reason documented. Only 50% (33) of the summaries reviewed had an indication for anticoagulation noted on the discharge summary and 91% of discharge summaries had a long term anticoagulant plan documented.ConclusionThe electronic prescribing system can help to ensure a clear anticoagulation communication as shown by 91% of the anticoagulation long term plan being clearly documented; making it a more seamless patient transfer. On the Philips PICU electronic prescribing system there is an anticoagulant section on the discharge summary that has 3 boxes that need to be completed; heparin regimen, indication and anticoagulation long term plan. However, despite these boxes; deviations from the anticoagulant protocol were poorly documented as highlighted by only 33% having the reason highlighted in the discharge summary, only 50% of the indications were documented. Despite having prompts for this information on the discharge summary, the medical staffs needs to be aware to complete this information, in order to reduce potential medication errors and risk.ReferenceThe National Patient Safety Agency (NPSA). Actions that make anticoagulant therapy safer. NPSA; March 2007.

scholarly journals Long-term lymphoid progenitors independently sustain naïve T and NK cell production in humans

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Natalia Izotova ◽  
Christine Rivat ◽  
Cristina Baricordi ◽  
Elena Blanco ◽  
Danilo Pellin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Gene Therapy ◽  
Nk Cell ◽  
Integration Site ◽  
Hematopoietic Stem ◽  
Cell Production ◽  
Lymphoid Progenitors ◽  
Clinical Gene Therapy ◽  
Cancer Immunotherapies

AbstractOur mathematical model of integration site data in clinical gene therapy supported the existence of long-term lymphoid progenitors capable of surviving independently from hematopoietic stem cells. To date, no experimental setting has been available to validate this prediction. We here report evidence of a population of lymphoid progenitors capable of independently maintaining T and NK cell production for 15 years in humans. The gene therapy patients of this study lack vector-positive myeloid/B cells indicating absence of engineered stem cells but retain gene marking in both T and NK. Decades after treatment, we can still detect and analyse transduced naïve T cells whose production is likely maintained by a population of long-term lymphoid progenitors. By tracking insertional clonal markers overtime, we suggest that these progenitors can support both T and NK cell production. Identification of these long-term lymphoid progenitors could be utilised for the development of next generation gene- and cancer-immunotherapies.

Sign in / Sign up

Export Citation Format

Share Document