scholarly journals The Role of Cysteine Peptidases in Hematopoietic Stem Cell Differentiation and Modulation of Immune System Function

2021 ◽  
Vol 12 ◽  
Author(s):  
Milica Perišić Nanut ◽  
Urša Pečar Fonović ◽  
Tanja Jakoš ◽  
Janko Kos
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Adaptive Immune Response ◽  
Stem Cell Differentiation ◽  
Functional Differentiation ◽  
Immune Functions ◽  
Hematopoietic Stem ◽  
Cysteine Cathepsins

Cysteine cathepsins are primarily involved in the degradation and recycling of proteins in endo-lysosomal compartments but are also gaining recognition as pivotal proteolytic contributors to various immune functions. Through their extracellular proteolytic activities within the hematopoietic stem cell niche, they are involved in progenitor cell mobilization and differentiation. Cysteine cathepsins, such as cathepsins L and S contribute to antigen-induced adaptive immunity through major histocompatibility complex class II antigen presentation whereas cathepsin X regulates T-cell migration. By regulating toll-like receptor signaling and cytokine secretion cysteine cathepsins activate innate immune cells and affect their functional differentiation. Cathepsins C and H are expressed in cytotoxic T lymphocytes and natural killer cells and are involved in processing of pro-granzymes into proteolytically active forms. Cytoplasmic activities of cathepsins B and L contribute to the maintenance of homeostasis of the adaptive immune response by regulating cell death of T and B lymphocytes. The expression pattern, localization, and activity of cysteine cathepsins is tightly connected to their function in immune cells. Furthermore, cysteine cathepsins together with their endogenous inhibitors, serve as mediators in the interplay between cancer and immune cells that results in immune cell anergy. The aim of the present article is to review the mechanisms of dysregulation of cysteine cathepsins and their inhibitors in relation to immune dysfunction to address new possibilities for regulation of their function.

scholarly journals Crosstalk between NOTCH and AKT signaling during murine megakaryocyte lineage specification

Blood ◽  
2011 ◽  
Vol 118 (5) ◽  
pp. 1264-1273 ◽  
Author(s):  
Melanie G. Cornejo ◽  
Vinciane Mabialah ◽  
Stephen M. Sykes ◽  
Tulasi Khandan ◽  
Cristina Lo Celso ◽  
...  
Keyword(s):  
Stem Cell ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Hematopoietic Stem Cell ◽  
Stem Cell Differentiation ◽  
Notch Signaling Pathway ◽  
Developmental Pathways ◽  
Lineage Specification ◽  
Hematopoietic Stem

Abstract The NOTCH signaling pathway is implicated in a broad range of developmental processes, including cell fate decisions. However, the molecular basis for its role at the different steps of stem cell lineage commitment is unclear. We recently identified the NOTCH signaling pathway as a positive regulator of megakaryocyte lineage specification during hematopoiesis, but the developmental pathways that allow hematopoietic stem cell differentiation into the erythro-megakaryocytic lineages remain controversial. Here, we investigated the role of downstream mediators of NOTCH during megakaryopoiesis and report crosstalk between the NOTCH and PI3K/AKT pathways. We demonstrate the inhibitory role of phosphatase with tensin homolog and Forkhead Box class O factors on megakaryopoiesis in vivo. Finally, our data annotate developmental mechanisms in the hematopoietic system that enable a decision to be made either at the hematopoietic stem cell or the committed progenitor level to commit to the megakaryocyte lineage, supporting the existence of 2 distinct developmental pathways.

scholarly journals Genome-wide analysis of promoter and enhancer usage in hematopoietic stem cell differentiation

2013 ◽  
Vol 6 (S1) ◽  
Author(s):  
Annarita Miccio ◽  
Clelia Peano ◽  
Oriana Romano ◽  
Guidantonio Tagliazucchi ◽  
Luca Petiti ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Differentiation ◽  
Hematopoietic Stem Cell ◽  
Stem Cell Differentiation ◽  
Hematopoietic Stem ◽  
Genome Wide Analysis ◽  
Genome Wide ◽  
Hematopoietic Stem Cell Differentiation

scholarly journals Daily Onset of Light and Darkness Differentially Controls Hematopoietic Stem Cell Differentiation and Maintenance

2018 ◽  
Vol 23 (4) ◽  
pp. 572-585.e7 ◽  
Author(s):  
Karin Golan ◽  
Anju Kumari ◽  
Orit Kollet ◽  
Eman Khatib-Massalha ◽  
Mohana Devi Subramaniam ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Differentiation ◽  
Hematopoietic Stem Cell ◽  
Stem Cell Differentiation ◽  
Hematopoietic Stem ◽  
Hematopoietic Stem Cell Differentiation

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.

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