scholarly journals A Stem Cell-Based Epigenetic Memory Mediates Interferon Response-Heterogeneity within the Hematopoietic System

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 634-634
Author(s):  
Simon Haas ◽  
Christoph Hirche ◽  
Alexandra Schnell ◽  
Can Sönmezer ◽  
Jens Langstein ◽  
...  
Keyword(s):  
Stem Cell ◽  
Immune Cells ◽  
Epigenetic Mechanism ◽  
Type I ◽  
Acute Type ◽  
Cell Type ◽  
Epigenetic Memory ◽  
Cell Level ◽  
Hematopoietic Stem ◽  
Wide Range

Abstract Mature blood and immune cells show broad inter- and intra-cell type-specific heterogeneity with respect to metabolic activity, gene expression patterns, differentiation capacity and responsiveness to cytokines such as interferons (IFNs). This diversity is of crucial importance to maintain the capacity of the immune system to appropriately react to a wide range of pathogenic insults, thereby mediating protective immunity. However, it remains poorly understood how such heterogeneity is generated and maintained. Until now, intra-cell type heterogeneity observed in blood and immune effector cells has mainly been attributed to extrinsic factors, such as differences in niche localization or cytokine exposure via paracrine signaling. Here, we show that intra-cell type heterogeneity can be established already at the stem cell-level and stably inherited to mature blood and immune cells through a stem cell-based epigenetic memory. Using distinct IFN reporter mouse models, we identified two subpopulations within the hematopoietic stem cell (HSC) compartment that strongly differ with regard to their IFN responsiveness (hereafter referred to as IFN-primed and IFN-non-primed HSCs). Serial transplantation of highly purified HSC subsets demonstrated that both IFN-primed and IFN-non-primed subpopulations are capable of driving long-term hematopoiesis. However, stem, progenitor and mature cells deriving from the two distinct HSC subsets stably inherited the IFN-priming status of their mother HSCs throughout serial rounds of transplantation. This suggested that IFN-priming heterogeneity observed in mature blood and immune cells is established at the stem cell level and inherited for thousands of cell generations. To investigate the consequences of the inherited IFN-priming state, we challenged mice with a broad spectrum of inflammatory cytokines, immunostimulants and viruses and subjected subpopulations to bulk and single-cell transcriptional profiling. Strikingly, populations with high IFN-priming mounted acute type-I IFN responses much more efficiently if compared to populations with low IFN-priming, suggesting that not only homeostatic IFN-priming but also responsiveness to acute IFNs is clonally determined at the stem cell level. Next, we investigated the signaling pathways regulating IFN-priming. For this purpose, we subjected HSCs of mice lacking key components of the IFN signaling and production pathways to molecular characterization. These analyses revealed that IFN-priming is driven by homeostatic, cell-intrinsic IFNAR/IFNGR-STAT1 and TNF-α signaling. To elucidate the molecular mechanism facilitating stable inheritance of IFN-priming, we performed extensive epigenetic profiling of IFN-primed and IFN-non-primed subpopulations. The results suggested that inheritance of IFN-priming is mediated by a novel epigenetic mechanism and associated with epigenetic pervasiveness versus silencing in IFN-primed and IFN-non-primed HSCs, respectively. Together, our data reveal a novel epigenetic stem cell-based memory that dictates IFN response heterogeneity in mature blood and immune cells. This finding will likely have far-reaching implications for the understanding of biological processes involved in antiviral responses, cancer immunosurveillance as well as autoimmunity. Disclosures No relevant conflicts of interest to declare.

scholarly journals Acute Kidney Injury and CKD Associated with Hematopoietic Stem Cell Transplantation

2019 ◽  
Vol 15 (2) ◽  
pp. 289-297 ◽  
Author(s):  
Amanda DeMauro Renaghan ◽  
Edgar A. Jaimes ◽  
Jolanta Malyszko ◽  
Mark A. Perazella ◽  
Ben Sprangers ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Thrombotic Microangiopathy ◽  
Kidney Injury ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Wide Range

Hematopoietic stem cell transplantation is a life-saving therapy for many patients with cancer, as well as patients with some nonmalignant hematologic disorders, such as aplastic anemia, sickle cell disease, and certain congenital immune deficiencies. Kidney injury directly associated with stem cell transplantation includes a wide range of structural and functional abnormalities, which may be vascular (hypertension, thrombotic microangiopathy), glomerular (albuminuria, nephrotic glomerulopathies), and/or tubulointerstitial. AKI occurs commonly after stem cell transplant, affecting 10%–73% of patients. The cause is often multifactorial and can include sepsis, nephrotoxic medications, marrow infusion syndrome, hepatic sinusoidal obstruction syndrome, thrombotic microangiopathy, infections, and graft versus host disease. The risk of post-transplant kidney injury varies depending on patient characteristics, type of transplant (allogeneic versus autologous), and choice of chemotherapeutic conditioning regimen (myeloablative versus nonmyeloablative). Importantly, AKI is associated with substantial morbidity, including the need for KRT in approximately 5% of patients and the development of CKD in up to 60% of transplant recipients. AKI has been associated universally with higher all-cause and nonrelapse mortality regardless of transplant type, and studies have consistently shown extremely high (>80%) mortality rates in those patients requiring acute dialysis. Accordingly, prevention, early recognition, and prompt treatment of kidney injury are essential to improving kidney and patient outcomes after hematopoietic stem cell transplantation, and for realizing the full potential of this therapy.

scholarly journals The Role of T Cells in Hematopoietic Stem Cell Engraftment

2006 ◽  
Vol 6 ◽  
pp. 246-253 ◽  
Author(s):  
Elizabeth Hexner
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Immune Cells ◽  
Immune Reconstitution ◽  
Host Immune System ◽  
Hematopoietic Stem ◽  
Cell Engraftment ◽  
Donor T Cells

Much attention has focused on the immune recovery of donor T cells following hematopoietic stem cell transplantation (HSCT). Termed immune reconstitution, a better understanding of the dynamics of the functional recovery of immune cells following HSCT has important implications both for fighting infections and, in the allogeneic setting, for providing antitumor activity while controlling graft-vs.-host disease (GVHD). The immune cells involved in immune reconstitution include antigen-presenting cells, B lymphocytes, natural killer cells, and, in particular, T lymphocytes, the immune cell that will be the subject of this review. In addition, T cells can play an important role in the process of engraftment of hematopoietic stem cells. The evidence for a T cell tropic effect on hematopoietic engraftment is both direct and indirect, and comes from the clinic as well as the research lab. Animal models have provided useful clues, but the molecular mechanisms that govern the interaction between donor stem cells, donor T cells, the host immune system, and the stem cell niche remain obscure. This review will describe the current published clinical and basic evidence related to T cells and stem cell engraftment, and will identify future directions for translational research in this area.

scholarly journals IL-2 and Anti-TGF-β Promote NK Cell Reconstitution and Anti-tumor Effects after Syngeneic Hematopoietic Stem Cell Transplantation

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3189 ◽  
Author(s):  
Maite Alvarez ◽  
Cordelia Dunai ◽  
Lam T. Khuat ◽  
Ethan G. Aguilar ◽  
Isabel Barao ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Nk Cells ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Immune Cells ◽  
Nk Cell ◽  
Continuous Treatment ◽  
Hematopoietic Stem

The failure of autologous hematopoietic stem cell transplantation (HSCT) has been associated with a profound immunodeficiency that follows shortly after treatment, which renders patients susceptible to opportunistic infections and/or cancer relapse. Thus, given the additional immunosuppressive pathways involved in immune evasion in cancer, strategies that induce a faster reconstitution of key immune effector cells are needed. Natural killer (NK) cells mediate potent anti-tumor effector functions and are the first immune cells to repopulate after HSCT. TGF-β is a potent immunosuppressive cytokine that can impede both the development and function of immune cells. Here, we evaluated the use of an immunotherapeutic regimen that combines low dose of IL-2, an NK cell stimulatory signal, with TGF-β neutralization, in order to accelerate NK cell reconstitution following congenic HSCT in mice by providing stimulatory signals yet also abrogating inhibitory ones. This therapy led to a marked expansion of NK cells and accelerated NK cell maturation. Following HSCT, mature NK cells from the treated recipients displayed an activated phenotype and enhanced anti-tumor responses both in vitro and in vivo. No overt toxicities or adverse effects were observed in the treated recipients. However, these stimulatory effects on NK cell recovery were predicated upon continuous treatment as cessation of treatment led to return to baseline levels and to no improvement of overall immune recovery when assessed at later time-points, indicating strict regulatory control of the NK cell compartment. Overall, this study still demonstrates that therapies that combine positive and negative signals can be plausible strategies to accelerate NK cell reconstitution following HSCT and augment anti-tumor efficacy.

Hematopoietic Stem Cell Transplantation for Autoimmune Disease

2020 ◽  
Vol 72 (1) ◽  
Author(s):  
Tobias Alexander ◽  
Raffaella Greco ◽  
John A. Snowden
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Autoimmune Diseases ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Publication Date ◽  
Hematopoietic Stem ◽  
Wide Range ◽  
Autologous Hsct

The introduction of targeted biologic therapies has changed the treatment landscape for autoimmune diseases (ADs) substantially, but although these therapies provide more specificity, they require continuous administration, rarely restore organ function or reverse disability, and are not curative. Over the last 25 years, hematopoietic stem cell transplantation (HSCT) has been increasingly used to treat patients in whom the risk:benefit ratio of HSCT is acceptable. In contrast to chronic suppression of immune function, this intensive one-off procedure aims to provide treatment-free remissions by the reinduction of self-tolerance. The European Society of Blood and Marrow Transplantation (EBMT) Autoimmune Diseases Working Party (ADWP) has been central to development of this approach, with over 3,300 HSCT registrations for ADs. Recent data have improved the evidence base to support autologous HSCT in multiple sclerosis, systemic sclerosis, and Crohn's disease, along with a wide range of rarer disease indications, and autologous HSCT has become an integral part of treatment algorithms in various ADs. Expected final online publication date for the Annual Review of Medicine, Volume 72 is January 27, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Bone Morphogenetic Proteins Regulate the Developmental Program of Human Hematopoietic Stem Cells

1999 ◽  
Vol 189 (7) ◽  
pp. 1139-1148 ◽  
Author(s):  
Mickie Bhatia ◽  
Dominique Bonnet ◽  
Dongmei Wu ◽  
Barbara Murdoch ◽  
Jeff Wrana ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Bone Morphogenetic Proteins ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Type I ◽  
Hematopoietic Tissue ◽  
Hematopoietic Stem ◽  
Proliferation And Differentiation

The identification of molecules that regulate human hematopoietic stem cells has focused mainly on cytokines, of which very few are known to act directly on stem cells. Recent studies in lower organisms and the mouse have suggested that bone morphogenetic proteins (BMPs) may play a critical role in the specification of hematopoietic tissue from the mesodermal germ layer. Here we report that BMPs regulate the proliferation and differentiation of highly purified primitive human hematopoietic cells from adult and neonatal sources. Populations of rare CD34+CD38−Lin− stem cells were isolated from human hematopoietic tissue and were found to express the BMP type I receptors activin-like kinase (ALK)-3 and ALK-6, and their downstream transducers SMAD-1, -4, and -5. Treatment of isolated stem cell populations with soluble BMP-2, -4, and -7 induced dose-dependent changes in proliferation, clonogenicity, cell surface phenotype, and multilineage repopulation capacity after transplantation in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Similar to transforming growth factor β, treatment of purified cells with BMP-2 or -7 at high concentrations inhibited proliferation yet maintained the primitive CD34+CD38− phenotype and repopulation capacity. In contrast, low concentrations of BMP-4 induced proliferation and differentiation of CD34+ CD38−Lin− cells, whereas at higher concentrations BMP-4 extended the length of time that repopulation capacity could be maintained in ex vivo culture, indicating a direct effect on stem cell survival. The discovery that BMPs are capable of regulating repopulating cells provides a new pathway for controlling human stem cell development and a powerful model system for studying the biological mechanism of BMP action using primary human cells.

scholarly journals Cellular Barcoding Links B-1a B Cell Potential to a Fetal Hematopoietic Stem Cell State at the Single-Cell Level

Immunity ◽  
2016 ◽  
Vol 45 (2) ◽  
pp. 346-357 ◽  
Author(s):  
Trine A. Kristiansen ◽  
Elin Jaensson Gyllenbäck ◽  
Alya Zriwil ◽  
Tomas Björklund ◽  
Jeremy A. Daniel ◽  
...  
Keyword(s):  
Stem Cell ◽  
B Cell ◽  
Single Cell ◽  
Hematopoietic Stem Cell ◽  
Single Cell Level ◽  
Cell Level ◽  
Cell Potential ◽  
Hematopoietic Stem ◽  
Stem Cell State ◽  
Cellular Barcoding

Allogeneic Hematopoietic Stem Cell Transplantation as Consolidation Therapy for Adult T Cell Leukemia/Lymphoma Patients: A Single-Center Experience in 35 Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5037-5037
Author(s):  
Shigeki Takemoto ◽  
Michihiro Hidaka ◽  
Shoichi Nagakura ◽  
Tatsunori Sakai ◽  
Takahiro Matsui ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Conditioning Regimen ◽  
Acute Type ◽  
Consolidation Therapy ◽  
Cell Leukemia ◽  
Hematopoietic Stem ◽  
Adult T Cell Leukemia ◽  
Lymphoma Type

Abstract Adult T cell leukemia/lymphoma (ATL) has a high incident in Japanese. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) against ATL made the patients’ survival longer than chemotherapy alone. Actually, some of them became long survivors (LS). The efficacy of allo-SCT for ATL was examined and the prognostic factors were discussed. We retrospectively surveyed the data of ATL patients who underwent allo-HSCT at our hospital between June 1997 and June 2007. The results of allo-HSCT in ATL patients (n=35) including acute type (n=18) and lymphoma-type (n=17) were analyzed retrospectively. Donors were HLA-related relation in 24 patients (69%) or unrelated volunteers in 11 patients (31%). Twelve patients (34%) were in complete remission (CR) before conditioning regimen. Twenty-one (60%) received a conventional stem cell transplantation (CST) and 14 (40%) received a reduced intensity stem cell transplantation (RIST). Because transplant related mortality (TRM) and relapse are mainly observed within day 100, we divided the patients into short survivors (SS) who died within day 100 and LS who were alive more than one year after allo-HSCT. The median survival time (MST) of SS and LS were 55.6 (10–99) days and 1241.3 (503–2492) days. Most of LS (8 of 10) showed CR as status of ATL before allo-HSCT and all LS were received CST but not RIST. Response of induction chemotherapy and following CST are important factors for the success of allo-HSCT for ATL as a promising consolidation therapy. Characteristics of patients ATL subtype Acute type Lymphoma-type 18 17 Gender Male Female 21 14 Age (range) 51.1 yo (41–61) ATL status CR PR PD Relapse 13 16 4 2 Conditioning regimen CST RIST 21 14 Stem cell source PB BM CB  Related 22 2 0  Unrelated 0 9 2 Short survivors TRM PD or Relapse  Related 8 5  Unrelated 5 1 Long survivors Alive Died  Related 6 2  Unrelated 2 0

Single-Centre Validation Of a Disease Risk Index For Estimating Survival and Relapse In Allogeneic Hematopoietic Stem Cell Transplant Recipients: Sample Size, Adequate Follow-Up, and Use Of Local Data Are Vital Considerations

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2143-2143
Author(s):  
Andrew B M Lim ◽  
Andrew W. Roberts ◽  
Kate Mason ◽  
Ashish R. Bajel ◽  
Jeffrey Szer ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Disease Risk ◽  
Risk Index ◽  
Local Data ◽  
Hematopoietic Stem ◽  
Training Cohort ◽  
Wide Range ◽  
Very High

Abstract Introduction Allogeneic hematopoietic stem cell transplantation (alloHSCT) is applied for a wide range of malignant hematologic diseases at a wide range of stages of activity, from durable complete remission to resistant relapse. Reporting transplant outcome by disease category alone, without considering disease activity, limits statistical analysis and interpretation of outcomes across time or institutions. Recently a tool for clustering different combinations of disease and disease stage – the Disease Risk Index (DRI) – was developed and validated to stratify for overall survival (OS), progression free survival (PFS) and cumulative incidence of relapse (CIR)1. Aims 1. To independently validate the DRI's ability to stratify patients for OS, PFS and CIR using data from our centre. 2. To determine if absolute estimates of OS, PFS and CIR derived from the original training cohort can be used to accurately predict OS, PFS and CIR for an independent, contemporaneous cohort. 3. To determine approximate thresholds of sample size and follow-up duration below which the DRI may fail to successfully stratify patients for OS, PFS and CIR. Methods From our institutional transplant database, we extracted data from 466 patients undergoing alloHSCT for hematologic malignancy at our institution between the years 2001 and 2011, with median survivor follow-up of 55.2 months (range 5.0-139.0) to validate and further explore the utility of the DRI. Data for time-to-event outcomes was locked for analysis on 14 February 2013. Results We identified that similar to the published findings, the DRI was able to significantly stratify for OS (at 4 years, OS for low DRI 81% [95% CI 70-94%]; intermediate DRI 68% [63-74%]; high DRI 41%, [32-51%]; very high DRI 0%; P < .001; see Figure 1), PFS (at 4 years, PFS for low DRI 72% [59-87%]; intermediate DRI 61% [55-67%]; high DRI 32% [24-42%]; very high DRI 0%; P < .001), and CIR (at 4 years, CIR for low DRI 14% [3-25%]; intermediate DRI 27% [21-32%]; high DRI 48% [39-57%]; not calculable for very high DRI; P < .001). The DRI was not predictive of non-relapse mortality (P = .379). The DRI retained its prognostic power when applied to subgroups of patients who received either myeloablative or non-ablative conditioning; non-T cell depleted transplants; and sibling donor transplants only. When compared with the original published training cohort, survival and relapse outcomes from a contemporaneous cohort (n = 324, alloHSCT between the years 2001 and 2008) from our institution were superior to those of the Boston cohort for low, intermediate and high DRI groups (4 year OS: low DRI 88% [95% CI 77-100%] vs 64% [56-70%]; intermediate DRI 68% [62-75%] vs 46% [42-50%]; high DRI 42% [33-53%] vs 26% [21-31%]; 4 year CIR: low DRI 12% [6-24%] vs 19% [13-24%]; intermediate DRI 26% [20-32%] vs 36% [33-40%]; high DRI 47% [37-57%] vs 55% [50-60%]). These findings underscore the importance of calibration with local data before using the DRI for predicting absolute rates of survival and relapse in individual institutions. To further explore if the DRI retained its power in smaller cohorts, we tested the DRI in smaller subsets of patients selected randomly from our data. We found the DRI successfully stratified a cohort of 100 patients (median survivor follow-up 51.1 months, range 8.5-139.0) for OS (P = .010), PFS (P = .016) and CIR (P = .027), but failed to stratify a cohort of 50 patients (median survivor follow-up 46.2 months, range 10.3-135.5) for survival (P = .385 for OS, P = .167 for PFS, P = .026 for CIR). Likewise, under simulated conditions of shorter follow-up, the DRI successfully stratified a cohort (n = 322) with median surviving follow-up of 40.6 months for OS and PFS, but failed to stratify a cohort (n = 242) with median surviving follow-up of 33.1 months. Conclusion We find the DRI to be a simple, practical and robust tool for pre-transplant risk stratification, and estimation of survival and relapse in alloHSCT recipients, when calibrated with local alloHSCT outcome data. However, users should be familiar with its limitations when applied to smaller cohorts or cohorts with shorter follow-up. References 1. Armand P, Gibson CJ, Cutler C et al. A disease risk index for patients undergoing allogeneic stem cell transplantation. Blood 2012;120:905-913. Disclosures: No relevant conflicts of interest to declare.

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