Many elderly people suffer from hematological diseases known to be highly age-dependent. Hematopoietic stem cells (HSCs) maintain the immune system by producing all blood cells throughout the ...lifetime of an organism. Recent reports have suggested that HSCs are susceptible to age-related stress and gradually lose their self-renewal and regeneration capacity with aging. HSC aging is driven by cell-intrinsic and -extrinsic factors that result in the disruption of the immune system. Thus, the study of HSC aging is important to our understanding of age-related immune diseases and can also provide potential strategies to improve quality of life in the elderly. In this review, we delineate our understanding of the phenotypes, causes, and molecular mechanisms involved in HSC aging.
Oxidative stress results from an imbalance between reactive oxygen species (ROS) production and antioxidant defense mechanisms. The regulation of stem cell self-renewal and differentiation is crucial ...for early development and tissue homeostasis. Recent reports have suggested that the balance between self-renewal and differentiation is regulated by the cellular oxidation-reduction (redox) state; therefore, the study of ROS regulation in regenerative medicine has emerged to develop protocols for regulating appropriate stem cell differentiation and maintenance for clinical applications. In this review, we introduce the defined roles of oxidative stress in pluripotent stem cells (PSCs) and hematopoietic stem cells (HSCs) and discuss the potential applications of pharmacological approaches for regulating oxidative stress in regenerative medicine.
Immunotherapy is extensively investigated for almost all types of hematologic tumors, from preleukemic to relapse/refractory malignancies. Due to the emergence of technologies for target cell ...characterization, antibody design and manufacturing, as well as genome editing, immunotherapies including gene and cell therapies are becoming increasingly elaborate and diversified. Understanding the tumor immune microenvironment of the target disease is critical, as is reducing toxicity. Although there have been many successes and newly FDA-approved immunotherapies for hematologic malignancies, we have learned that insufficient efficacy due to disease relapse following treatment is one of the key obstacles for developing successful therapeutic regimens. Thus, combination therapies are also being explored. In this review, immunotherapies for each type of hematologic malignancy will be introduced, and novel targets that are under investigation will be described.
The regulation of hematopoietic stem cell (HSC) fate decision, whether they keep quiescence, self-renew, or differentiate into blood lineage cells, is critical for maintaining the immune system ...throughout one's lifetime. As HSCs are exposed to age-related stress, they gradually lose their self-renewal and regenerative capacity. Recently, many reports have implicated signaling pathways in the regulation of HSC fate determination and malignancies under aging stress or pathophysiological conditions. In this review, we focus on the current understanding of signaling pathways that regulate HSC fate including quiescence, self-renewal, and differentiation during aging, and additionally introduce pharmacological approaches to rescue defects of HSC fate determination or hematopoietic malignancies by kinase signaling pathways.
Schwann cells play a crucial role in successful nerve repair and regeneration by supporting both axonal growth and myelination. However, the sources of human Schwann cells are limited both for ...studies of Schwann cell development and biology and for the development of treatments for Schwann cell-associated diseases. Here, we provide a rapid and scalable method to produce self-renewing Schwann cell precursors (SCPs) from human pluripotent stem cells (hPSCs), using combined sequential treatment with inhibitors of the TGF-β and GSK-3 signaling pathways, and with neuregulin-1 for 18 days under chemically defined conditions. Within 1 week, hPSC-derived SCPs could be differentiated into immature Schwann cells that were functionally confirmed by their secretion of neurotrophic factors and their myelination capacity in vitro and in vivo. We propose that hPSC-derived SCPs are a promising, unlimited source of functional Schwann cells for treating demyelination disorders and injuries to the peripheral nervous system.
•hPSC-SCPs are highly expandable under chemically defined medium condition•hPSC-SCPs can rapidly and efficiently differentiate into functional Schwann cells•SCP-SCs myelinate axon and secrete various neurotrophic factors•SCP-SCs promote axonal regeneration in sciatic nerve-damaged mice
In this article, Cho and colleagues show that an efficient strategy for producing directly an unlimited supply of functional human Schwann cells (SCs) via successful derivation of expandable Schwann cell precursors (SCPs) from human pluripotent stem cells (hPSC-SCPs). Functional and molecular characteristic of SCs from hPSC-SCPs (SCP-SCs) were shown both in vitro and in vivo.
OCT-4 transcription factors play an important role in maintaining the pluripotent state of embryonic stem cells and may prevent expression of genes activated during differentiation. Human OCT-4 ...isoform mRNAs encode proteins that have identical POU DNA binding domains and C-terminal domains but differ in their N-terminal domains. We report here the cloning and characterization of the human OCT-4B isoform. Human OCT-4B cDNA encodes a 265-amino acid protein with a predicted molecular mass of 30 kDa. Embryonic stem (E14141) cell-based complementation assays using ZHBTc4 ES cells showed that unlike human OCT-4A, OCT-4B cannot sustain ES cell self-renewal. In addition, OCT-4B does not bind to a probe carrying the OCT-4 consensus binding sequence, and we demonstrate that two separate regions of its N-terminal domain are responsible for inhibiting DNA binding. We also demonstrate that OCT-4B is mainly localized to the cytoplasm. Overexpression of OCT-4B did not activate transcription from OCT-4-dependent promoters, although OCT-4A did as reported previously. Furthermore, transcriptional activation by human OCT-4A was not inhibited by co-expression of OCT-4B. Taken together, these data suggest that the DNA binding, transactivation, and abilities to confer self-renewal of the human OCT-4 isoforms differ.
Mouse and human ES (embryonic stem) cells display unusual proliferative properties and can produce pluripotent stem cells indefinitely. Both processes might be important for maintaining the ...'stemness' of ES cells; however, little is known about how the cell-cycle fate is regulated in ES cells. Oct-4, a master switch of pluripotency, plays an important role in maintaining the pluripotent state of ES cells and may prevent the expression of genes activated during differentiation. Using ZHBTc4 ES cells, we have investigated the effect of Oct-4 on ES cell-cycle control, and we found that Oct-4 down-regulation in ES cells inhibits proliferation by blocking cell-cycle progression in G0/G1. Deletion analysis of the functional domains of Oct-4 indicates that the overall integrity of the Oct-4 functional domains is important for the stimulation of S-phase entry. We also show in the present study that the p21 gene is a target for Oct-4 repression. Furthermore, p21 protein levels were repressed by Oct-4 and were induced by the down-regulation of Oct-4 in ZHBTc4 ES cells. Therefore the down-regulation of p21 by Oct-4 may contribute to the maintenance of ES cell proliferation.
Protein kinases modulate the reversible postmodifications of substrate proteins to their phosphorylated forms as an essential process in regulating intracellular signaling transduction cascades. ...Moreover, phosphorylation has recently been shown to tightly control the regulatory network of kinases responsible for the induction and maintenance of pluripotency, defined as the particular ability to differentiate pluripotent stem cells (PSCs) into every cell type in the adult body. In particular, emerging evidence indicates that the balance between the self-renewal and differentiation of PSCs is regulated by the small molecules that modulate kinase signaling pathways. Furthermore, new reprogramming technologies have been developed using kinase modulators, which have provided novel insight of the mechanisms underlying the kinase regulatory networks involved in the generation of induced pluripotent stem cells (iPSCs). In this review, we highlight the recent progress made in defining the roles of protein kinase signaling pathways and their small molecule modulators in regulating the pluripotent states, self-renewal, reprogramming process, and lineage differentiation of PSCs.
Shiga toxins (Stxs) produced by enterohemorrhagic Escherichia coli (EHEC) are the major virulence factors responsible for hemorrhagic colitis, which can lead to life‐threatening systemic ...complications including acute renal failure (hemolytic uremic syndrome) and neuropathy. Here, we report that O‐GlcNAcylation, a type of post‐translational modification, was acutely increased upon induction of endoplasmic reticulum (ER) stress in host cells by Stxs. Suppression of the abnormal Stx‐mediated increase in O‐GlcNAcylation effectively inhibited apoptotic and inflammatory responses in Stx‐susceptible cells. The protective effect of O‐GlcNAc inhibition for Stx‐mediated pathogenic responses was also verified using three‐dimensional (3D)‐cultured spheroids or organoids mimicking the human kidney. Treatment with an O‐GlcNAcylation inhibitor remarkably improved the major disease symptoms and survival rate for mice intraperitoneally injected with a lethal dose of Stx. In conclusion, this study elucidates O‐GlcNAcylation‐dependent pathogenic mechanisms of Stxs and demonstrates that inhibition of aberrant O‐GlcNAcylation is a potential approach to treat Stx‐mediated diseases.
Synopsis
Here we identify a previously unknown link between the O‐GlcNAcylation pathway and the pathogenesis of enterohemorrhagic E. coli Shiga toxin‐mediated diseases. Given the capacity of these bacterial toxins to subvert normal cellular regulation in the host, this study demonstrates that Shiga toxins alter O‐GlcNAcylation, a type of post‐translational modification, to exacerbate dysfunction in host cell signaling.
Shiga toxins induce acute elevations of O‐GlcNAcylation levels which exacerbate host cell damage in vitro and lethality in mice.
Shiga toxin‐induced O‐GlcNAcylation increases apoptosis and inflammation through Akt and p‐65, respectively, in toxin‐susceptible cells and human kidney spheroid or organoid surrogate renal model systems.
Inhibition of elevated O‐GlcNAcylation levels may represent a therapeutic target to ameliorate Shiga toxin‐mediated pathogenesis.
Here we identify a previously unknown link between the O‐GlcNAcylation pathway and the pathogenesis of enterohemorrhagic E. coli Shiga toxin‐mediated diseases. Given the capacity of these bacterial toxins to subvert normal cellular regulation in the host, this study demonstrates that Shiga toxins alter O‐GlcNAcylation, a type of post‐translational modification, to exacerbate dysfunction in host cell signaling.
The function of natural killer (NK) cell-derived interferon-γ (IFN-γ) expands to remove pathogens by increasing the ability of innate immune cells. Here, we identified the critical role of ...thioredoxin-interacting protein (TXNIP) in the production of IFN-γ in NK cells during bacterial infection. TXNIP inhibited the production of IFN-γ and the activation of transforming growth factor β-activated kinase 1 (TAK1) activity in primary mouse and human NK cells. TXNIP directly interacted with TAK1 and inhibited TAK1 activity by interfering with the complex formation between TAK1 and TAK1 binding protein 1 (TAB1).
(KO) NK cells enhanced the activation of macrophages by inducing IFN-γ production during Pam3CSK4 stimulation or Staphylococcus aureus (
) infection and contributed to expedite the bacterial clearance. Our findings suggest that NK cell-derived IFN-γ is critical for host defense and that TXNIP plays an important role as an inhibitor of NK cell-mediated macrophage activation by inhibiting the production of IFN-γ during bacterial infection.
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