Publications by authors named "Mariusz Z Ratajczak"

299 Publications

Innate Immunity Communicates Using the Language of Extracellular Microvesicles.

Stem Cell Rev Rep 2021 Feb 25. Epub 2021 Feb 25.

Department of Regenerative Medicine, Center for Preclinical Research and Technology, Medical University of Warsaw, Warszawa, Poland.

The innate immunity system and extracellular microvesicles (ExMVs) both emerged early in the evolution of life, which is why its innate immunity cellular arm and its soluble-component arm learned, understood, and adapted to the "language" of ExMVs. This was most likely the first language of cell-cell communication during evolution, which existed before more specific intercellular crosstalk involving specific ligands and receptors emerged. ExMVs are involved in several processes in the body, including immune and coagulation responses, which are part of inflammation. In this review we will briefly highlight what is known about how ExMVs regulate the function of the cellular arm of innate immunity, including macrophages, monocytes, granulocytes, natural killer cells, and dendritic cells, and affect the soluble components of this system, which consists of the complement cascade (ComC) and soluble, circulating, pattern-recognition receptors (collectins, ficolins, and pentaxrins). These effects are direct, due to the fact that ExMVs affect the biological functions of innate immunity cells and may directly interact with soluble components of this system. Moreover, by activating coagulation proteases, ExMVs may also indirectly activate the ComC. In this review, we will use the term "extracellular microvesicles" (ExMVs) to refer to these small, spheroidal blebs of different sizes, which are surrounded by a membrane lipid layer. We will focus on the role of both ExMVs released during cell-surface membrane budding and smaller ExMVs, known as exosomes, which are derived from the budding of the endosomal membrane compartment. Finally, we will provide a brief update on the potential therapeutic applications of ExMVs, with a special emphasis on innate immunity.
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http://dx.doi.org/10.1007/s12015-021-10138-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906088PMC
February 2021

Danger-associated molecular pattern molecules take unexpectedly a central stage in Nlrp3 inflammasome-caspase-1-mediated trafficking of hematopoietic stem/progenitor cells.

Leukemia 2021 Feb 23. Epub 2021 Feb 23.

Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.

Like their homing after transplantation to bone marrow (BM), the mobilization of hematopoietic stem/progenitor cells (HSPCs) is still not fully understood, and several overlapping pathways are involved. Several years ago our group proposed that sterile inflammation in the BM microenvironment induced by pro-mobilizing agents is a driving force in this process. In favor of our proposal, both complement cascade (ComC)-deficient and Nlrp3 inflammasome-deficient mice are poor G-CSF and AMD3100 mobilizers. It is also known that the Nlrp3 inflammasome mediates its effects by activating caspase-1, which is responsible for proteolytic activation of interleukin-1β (IL-1β) and interleukin-18 (IL-18) and their release from cells along with several danger-associated molecular pattern molecules (DAMPs). We observed in the past that IL-1β and IL-18 independently promote mobilization of HSPCs. In the current work we demonstrated that caspase-1-KO mice are poor mobilizers, and, to our surprise, administration of IL-1β or IL-18, as in the case of Nlrp3-KO animals, does not correct this defect. Moreover, neither Caspase-1-KO nor Nlrp3-KO mice properly activated the ComC to execute the mobilization process. Interestingly, mobilization in these animals and activation of the ComC were both restored after injection of the DAMP cocktail eATP+HGMB1+S100A9, the components of which are normally released from cells in an Nlrp3 inflammasome-caspase-1-dependent manner. In addition, we report that caspase-1-deficient HSPCs show a decrease in migration in response to BM homing factors and engraft more poorly after transplantation. These results for the first time identify caspase-1 as an orchestrator of HSPC trafficking.
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http://dx.doi.org/10.1038/s41375-021-01158-9DOI Listing
February 2021

Extracellular Adenosine Triphosphate (eATP) and Its Metabolite, Extracellular Adenosine (eAdo), as Opposing "Yin-Yang" Regulators of Nlrp3 Inflammasome in the Trafficking of Hematopoietic Stem/Progenitor Cells.

Front Immunol 2020 29;11:603942. Epub 2021 Jan 29.

Stem Cell Institute at Division of Hematology, Department of Medicine and James Graham Brown Cancer Center, University of Louisville, KY, United States.

Nlrp3 inflammasome plays a pleiotropic role in hematopoietic cells. On the one hand, physiological activation of this intracellular protein complex is crucial to maintaining normal hematopoiesis and the trafficking of hematopoietic stem progenitor cells (HSPCs). On the other hand, its hyperactivation may lead to cell death by pyroptosis, and prolonged activity is associated with sterile inflammation of the BM and, as a consequence, with the HSPCs aging and origination of myelodysplasia and leukemia. Thus, we need to understand better this protein complex's actions to define the boundaries of its safety window and study the transition from being beneficial to being detrimental. As demonstrated, the Nlrp3 inflammasome is expressed and active both in HSPCs and in the non-hematopoietic cells that are constituents of the bone marrow (BM) microenvironment. Importantly, the Nlrp3 inflammasome responds to mediators of purinergic signaling, and while extracellular adenosine triphosphate (eATP) activates this protein complex, its metabolite extracellular adenosine (eAdo) has the opposite effect. In this review, we will discuss and focus on the physiological consequences of the balance between eATP and eAdo in regulating the trafficking of HSPCs in an Nlrp3 inflammasome-dependent manner, as seen during pharmacological mobilization from BM into peripheral blood (PB) and in the reverse mechanism of homing from PB to BM and engraftment. We propose that both mediators of purinergic signaling and the Nlrp3 inflammasome itself may become important therapeutic targets in optimizing the trafficking of HSPCs in clinical settings.
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http://dx.doi.org/10.3389/fimmu.2020.603942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878390PMC
January 2021

P2Y14 Receptor as a Target for Neutrophilia Attenuation in Severe COVID-19 Cases: From Hematopoietic Stem Cell Recruitment and Chemotaxis to Thrombo-inflammation.

Stem Cell Rev Rep 2021 02 11;17(1):241-252. Epub 2021 Feb 11.

Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748. Sala 964 Bloco 9 Superior, Cidade Universitária, São Paulo, SP, 05508-000, Brazil.

The global SARS-CoV-2 pandemic starting in 2019 has already reached more than 2.3 million deaths. Despite the scientific community's efforts to investigate the COVID-19 disease, a drug for effectively treating or curing patients yet needs to be discovered. Hematopoietic stem cells (HSC) differentiating into immune cells for defense express COVID-19 entry receptors, and COVID-19 infection hinders their differentiation. The importance of purinergic signaling in HSC differentiation and innate immunity has been recognized. The metabotropic P2Y14 receptor subtype, activated by UDP-glucose, controls HSC differentiation and mobilization. Thereon, the exacerbated activation of blood immune cells amplifies the inflammatory state observed in COVID-19 patients, specially through the continuous release of reactive oxygen species and extracellular neutrophil traps (NETs). Further, the P2Y14 subtype, robustly inhibits the infiltration of neutrophils into various epithelial tissues, including lungs and kidneys. Here we discuss findings suggesting that antagonism of the P2Y14 receptor could prevent the progression of COVID-19-induced systemic inflammation, which often leads to severe illness and death cases. Considering the modulation of neutrophil recruitment of extreme relevance for respiratory distress and lung failure prevention, we propose that P2Y14 receptor inhibition by its selective antagonist PPTN could limit neutrophil recruitment and NETosis, hence limiting excessive formation of oxygen reactive species and proteolytic activation of the kallikrein-kinin system and subsequent bradykinin storm in the alveolar septa of COVID-19 patients.
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http://dx.doi.org/10.1007/s12015-021-10129-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877512PMC
February 2021

Stem Cells as Potential Therapeutics and Targets for Infection by COVID19 - Special Issue on COVID19 in Stem Cell Reviews and Reports.

Stem Cell Rev Rep 2021 Feb;17(1):1-3

University of Louisville, Louisville, KY, USA.

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http://dx.doi.org/10.1007/s12015-020-10116-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796808PMC
February 2021

Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology.

Mol Psychiatry 2020 Dec 16. Epub 2020 Dec 16.

Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil.

Scientists and health professionals are exhaustively trying to contain the coronavirus disease 2019 (COVID-19) pandemic by elucidating viral invasion mechanisms, possible drugs to prevent viral infection/replication, and health cares to minimize individual exposure. Although neurological symptoms are being reported worldwide, neural acute and long-term consequences of SARS-CoV-2 are still unknown. COVID-19 complications are associated with exacerbated immunoinflammatory responses to SARS-CoV-2 invasion. In this scenario, pro-inflammatory factors are intensely released into the bloodstream, causing the so-called "cytokine storm". Both pro-inflammatory factors and viruses may cross the blood-brain barrier and enter the central nervous system, activating neuroinflammatory responses accompanied by hemorrhagic lesions and neuronal impairment, which are largely described processes in psychiatric disorders and neurodegenerative diseases. Therefore, SARS-CoV-2 infection could trigger and/or worse brain diseases. Moreover, patients with central nervous system disorders associated to neuroimmune activation (e.g. depression, Parkinson's and Alzheimer's disease) may present increased susceptibility to SARS-CoV-2 infection and/or achieve severe conditions. Elevated levels of extracellular ATP induced by SARS-CoV-2 infection may trigger hyperactivation of P2X7 receptors leading to NLRP3 inflammasome stimulation as a key mediator of neuroinvasion and consequent neuroinflammatory processes, as observed in psychiatric disorders and neurodegenerative diseases. In this context, P2X7 receptor antagonism could be a promising strategy to prevent or treat neurological complications in COVID-19 patients.
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http://dx.doi.org/10.1038/s41380-020-00965-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738776PMC
December 2020

Heme Oxygenase 1 (HO-1) as an Inhibitor of Trafficking of Normal and Malignant Hematopoietic Stem Cells - Clinical and Translational Implications.

Stem Cell Rev Rep 2020 Nov 16. Epub 2020 Nov 16.

Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY, 40202, USA.

Evidence indicates that bone marrow (BM)-residing hematopoietic stem/progenitor cells (HSPCs) are released into peripheral blood (PB) after administration of pro-mobilizing drugs, which induce a state of sterile inflammation in the BM microenvironment. In the reverse process, as seen after hematopoietic transplantation, intravenously injected HSPCs home and engraft into BM niches. Here again, conditioning for transplantation by myeloablative chemo- or radiotherapy induces a state of sterile inflammation that promotes HSPC seeding to BM stem cell niches. Therefore, the trafficking of HSPCs and their progeny, including granulocytes and monocytes/macrophages, is regulated by a response to pro-inflammatory stimuli. This responsiveness to inflammatory cues is also preserved after malignant transformation of hematopoietic cells. Results from our laboratory indicate that the responsiveness of hematopoietic cells to pro-inflammatory stimuli is orchestrated by Nlrp3 inflammasome. As reported, HO-1 effectively attenuates intracellular activation of Nlrp3 inflammasome as well as the pro-inflammatory effects of several humoral mediators, including complement cascade (ComC) cleavage fragments that promote migration of hematopoietic cells. Based on this finding, inhibition of HO-1 activity may become a practical strategy to enhance the mobilization and homing of normal HSPCs, and, alternatively, its activation may prevent unwanted spread and in vivo expansion of leukemic cells. Graphical Abstract.
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http://dx.doi.org/10.1007/s12015-020-10083-wDOI Listing
November 2020

Paper of the December Issue of Stem Cell Reviews and Reports Presents a Comprehensive Review of the Current Knowledge on Complexity of Hematopoietic Stem Cell Aging.

Stem Cell Rev Rep 2020 12;16(6):1019

University of Louisville, Louisville, KY, USA.

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http://dx.doi.org/10.1007/s12015-020-10066-xDOI Listing
December 2020

Extracellular microvesicles/exosomes: discovery, disbelief, acceptance, and the future?

Leukemia 2020 12 14;34(12):3126-3135. Epub 2020 Sep 14.

Stem Cell Institute, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.

There are concepts in science that need time to overcome initial disbelief before finally arriving at the moment when they are embraced by the research community. One of these concepts is the biological meaning of the small, spheroidal vesicles released from cells, which are described in the literature as microparticles, microvesicles, or exosomes. In the beginning, this research was difficult, as it was hard to distinguish these small vesicles from cell debris or apoptotic bodies. However, they may represent the first language of cell-cell communication, which existed before a more specific intercellular cross-talk between ligands and receptors emerged during evolution. In this review article, we will use the term "extracellular microvesicles" (ExMVs) to refer to these small spheroidal blebs of different sizes surrounded by a lipid layer of membrane. We have accepted an invitation from the Editor-in-Chief to write this review in observance of the 20th anniversary of the 2001 ASH Meeting when our team demonstrated that, by horizontal transfer of several bioactive molecules, including mRNA species and proteins, ExMVs harvested from embryonic stem cells could modify hematopoietic stem/progenitor cells and expand them ex vivo. Interestingly, the result that moved ExMV research forward was published first in 2005 in Leukemia, having been previously rejected by other major scientific journals out of simple disbelief. Therefore, the best judge of a new concept is the passage of time, although the speed of its adoption is aided by perseverance and confidence in one's own data. In this perspective article, we will provide a brief update on the current status of, hopes for, and likely future of ExMV research as well as therapeutic and diagnostic applications, with a special emphasis on hematopoiesis.
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http://dx.doi.org/10.1038/s41375-020-01041-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685969PMC
December 2020

Correction: Withaferin A (WFA) inhibits tumor growth and metastasis by targeting ovarian cancer stem cells.

Oncotarget 2020 Aug 11;11(32):3103-3104. Epub 2020 Aug 11.

Department of Medicine, University of Louisville, Louisville, KY 40202, USA.

[This corrects the article DOI: 10.18632/oncotarget.20170.].
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http://dx.doi.org/10.18632/oncotarget.27597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429178PMC
August 2020

SARS-CoV-2 Entry Receptor ACE2 Is Expressed on Very Small CD45 Precursors of Hematopoietic and Endothelial Cells and in Response to Virus Spike Protein Activates the Nlrp3 Inflammasome.

Stem Cell Rev Rep 2021 02;17(1):266-277

Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY, 40202, USA.

Angiotensin-converting enzyme 2 (ACE2) plays an important role as a member of the renin-angiotensin-aldosterone system (RAAS) in regulating the conversion of angiotensin II (Ang II) into angiotensin (1-7) (Ang [1-7]). But at the same time, while expressed on the surface of human cells, ACE2 is the entry receptor for SARS-CoV-2. Expression of this receptor has been described in several types of cells, including hematopoietic stem cells (HSCs) and endothelial progenitor cells (EPCs), which raises a concern that the virus may infect and damage the stem cell compartment. We demonstrate for the first time that ACE2 and the entry-facilitating transmembrane protease TMPRSS2 are expressed on very small CD133CD34LinCD45 cells in human umbilical cord blood (UCB), which can be specified into functional HSCs and EPCs. The existence of these cells known as very small embryonic-like stem cells (VSELs) has been confirmed by several laboratories, and some of them may correspond to putative postnatal hemangioblasts. Moreover, we demonstrate for the first time that, in human VSELs and HSCs, the interaction of the ACE2 receptor with the SARS-CoV-2 spike protein activates the Nlrp3 inflammasome, which if hyperactivated may lead to cell death by pyroptosis. Based on this finding, there is a possibility that human VSELs residing in adult tissues could be damaged by SARS-CoV-2, with remote effects on tissue/organ regeneration. We also report that ACE2 is expressed on the surface of murine bone marrow-derived VSELs and HSCs, although it is known that murine cells are not infected by SARS-CoV-2. Finally, human and murine VSELs express several RAAS genes, which sheds new light on the role of these genes in the specification of early-development stem cells. Graphical Abstract •Human VSELs and HSCs express ACE2 receptor for SARS-CoV2 entry. •Interaction of viral spike protein with ACE2 receptor may hyperactivate Nlrp3 inflammasome which induces cell death by pyroptosis. •SARS-CoV2 may also enter cells and eliminate them by cell lysis. •What is not shown since these cells express also Ang II receptor they may hyperactivate Nlrp3 inflammasome in response to Ang II which may induce pyroptosis. Our data indicates that Ang 1-7 may have a protective effect.
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http://dx.doi.org/10.1007/s12015-020-10010-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370872PMC
February 2021

Nlrp3 Inflammasome Signaling Regulates the Homing and Engraftment of Hematopoietic Stem Cells (HSPCs) by Enhancing Incorporation of CXCR4 Receptor into Membrane Lipid Rafts.

Stem Cell Rev Rep 2020 Oct;16(5):954-967

Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY, 40202, USA.

Fast and efficient homing and engraftment of hematopoietic stem progenitor cells (HSPCs) is crucial for positive clinical outcomes from transplantation. We found that this process depends on activation of the Nlrp3 inflammasome, both in the HSPCs to be transplanted and in the cells in the recipient bone marrow (BM) microenvironment. For the first time we provide evidence that functional deficiency in the Nlrp3 inflammasome in transplanted cells or in the host microenvironment leads to defective homing and engraftment. At the molecular level, functional deficiency of the Nlrp3 inflammasome in HSPCs leads to their defective migration in response to the major BM homing chemoattractant stromal-derived factor 1 (SDF-1) and to other supportive chemoattractants, including sphingosine-1-phosphate (S1P) and extracellular adenosine triphosphate (eATP). We report that activation of the Nlrp3 inflammasome increases autocrine release of eATP, which promotes incorporation of the CXCR4 receptor into membrane lipid rafts at the leading surface of migrating cells. On the other hand, a lack of Nlrp3 inflammasome expression in BM conditioned for transplantation leads to a decrease in expression of SDF-1 and danger-associated molecular pattern molecules (DAMPs), which are responsible for activation of the complement cascade (ComC), which in turn facilitates the homing and engraftment of HSPCs.
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http://dx.doi.org/10.1007/s12015-020-10005-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456406PMC
October 2020

Markers of Regenerative Processes in Patients with Bipolar Disorder: A Case-control Study.

Brain Sci 2020 Jun 30;10(7). Epub 2020 Jun 30.

Department of Psychiatry, Pomeranian University of Medicine, 71-460 Szczecin, Poland.

Progress in medical science has allowed the discovery of many factors affecting the pathogenesis of bipolar disorder, and among the most recent research directions are found regenerative and inflammatory processes. The role of regenerative processes remains particularly poorly explored, but available data encourage further research, which may explain the pathogenesis of bipolar disorder (BD). The aim of this study was to evaluate the mobilization of stem cells into peripheral blood, in patients with bipolar disorder during stable phase, not treated with lithium salts. The study included 30 unrelated individuals with the diagnosis of bipolar disorder, with disease duration of at least 10 years, not treated with lithium salts for at least five years prior to the study. The control group consisted of 30 healthy subjects, matched for age, sex, body mass index (BMI), origin, socio-demographic factors and nicotine use. Blood samples underwent cytometric analyses to assess concentrations of: Very Small Embryonic Like (VSEL) CD34+, VSEL AC133+, HSC CD34+, HSC AC133+. There were no significant differences in stem cell levels between patients with BD and healthy controls. However, the level of VSEL cells AC133 + was significantly higher in type I BD patients compared to healthy controls. Our results indicate a disturbance in regenerative processes in patients with bipolar disorder.
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http://dx.doi.org/10.3390/brainsci10070408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408571PMC
June 2020

Paper of the August Issue of Stem Cell Reviews and Reports Reveals a Novel Role of Bone Marrow Stroma Cells Expressed CXCR4 in Preventing Aging of Hematopoietic Stem/Progenitor Cells.

Stem Cell Rev Rep 2020 Aug;16(4):627

University of Louisville, Louisville, KY, USA.

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http://dx.doi.org/10.1007/s12015-020-09997-2DOI Listing
August 2020

Pannexin-1 channel "fuels" by releasing ATP from bone marrow cells a state of sterile inflammation required for optimal mobilization and homing of hematopoietic stem cells.

Purinergic Signal 2020 09 12;16(3):313-325. Epub 2020 Jun 12.

Center for Preclinical Studies and Technology, Department of Regenerative Medicine, Medical University of Warsaw, ul. Żwirki i Wigury 61, 02-091, Warsaw, Poland.

An efficient harvest of hematopoietic stem/progenitor cells (HSPCs) after pharmacological mobilization from the bone marrow (BM) into peripheral blood (PB) and subsequent proper homing and engraftment of these cells are crucial for clinical outcomes from hematopoietic transplants. Since extracellular adenosine triphosphate (eATP) plays an important role in both processes as an activator of sterile inflammation in the bone marrow microenvironment, we focused on the role of Pannexin-1 channel in the secretion of ATP to trigger both egress of HSPCs out of BM into PB as well as in reverse process that is their homing to BM niches after transplantation into myeloablated recipient. We employed a specific blocking peptide against Pannexin-1 channel and noticed decreased mobilization efficiency of HSPCs as well as other types of BM-residing stem cells including mesenchymal stroma cells (MSCs), endothelial progenitors (EPCs), and very small embryonic-like stem cells (VSELs). To explain better a role of Pannexin-1, we report that eATP activated Nlrp3 inflammasome in Gr-1 and CD11b cells enriched for granulocytes and monocytes. This led to release of danger-associated molecular pattern molecules (DAMPs) and mitochondrial DNA (miDNA) that activate complement cascade (ComC) required for optimal egress of HSPCs from BM. On the other hand, Pannexin-1 channel blockage in transplant recipient mice leads to a defect in homing and engraftment of HSPCs. Based on this, Pannexin-1 channel as a source of eATP plays an important role in HSPCs trafficking.
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http://dx.doi.org/10.1007/s11302-020-09706-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524928PMC
September 2020

SARS-CoV-2 infection and overactivation of Nlrp3 inflammasome as a trigger of cytokine "storm" and risk factor for damage of hematopoietic stem cells.

Leukemia 2020 07 1;34(7):1726-1729. Epub 2020 Jun 1.

Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Kentucky, USA.

The scientific community faces an unexpected and urgent challenge related to the SARS-CoV-2 pandemic and is investigating the role of receptors involved in entry of this virus into cells as well as pathomechanisms leading to a cytokine "storm," which in many cases ends in severe acute respiratory syndrome, fulminant myocarditis and kidney injury. An important question is if it may also damage hematopoietic stem progenitor cells?
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http://dx.doi.org/10.1038/s41375-020-0887-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262681PMC
July 2020

Innate immunity orchestrates the mobilization and homing of hematopoietic stem/progenitor cells by engaging purinergic signaling-an update.

Purinergic Signal 2020 06 15;16(2):153-166. Epub 2020 May 15.

Department of Biochemistry, Institute of Chemistry, University of São Paulo, Av. Professor Lineu Prestes 748, Sao Paulo, SP, 05508-000, Brazil.

Bone marrow (BM) as an active hematopoietic organ is highly sensitive to changes in body microenvironments and responds to external physical stimuli from the surrounding environment. In particular, BM tissue responds to several cues related to infections, strenuous exercise, tissue/organ damage, circadian rhythms, and physical challenges such as irradiation. These multiple stimuli affect BM cells to a large degree through a coordinated response of the innate immunity network as an important guardian for maintaining homeostasis of the body. In this review, we will foc++us on the role of purinergic signaling and innate immunity in the trafficking of hematopoietic stem/progenitor cells (HSPCs) during their egression from the BM into peripheral blood (PB), as seen along pharmacological mobilization, and in the process of homing and subsequent engraftment into BM after hematopoietic transplantation. Innate immunity mediates these processes by engaging, in addition to certain peptide-based factors, other important non-peptide mediators, including bioactive phosphosphingolipids and extracellular nucleotides, as the main topic of this review. Elucidation of these mechanisms will allow development of more efficient stem cell mobilization protocols to harvest the required number of HSPCs for transplantation and to accelerate hematopoietic reconstitution in transplanted patients.
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http://dx.doi.org/10.1007/s11302-020-09698-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367963PMC
June 2020

A Novel Evidence That Mannan Binding Lectin (MBL) Pathway of Complement Cascade Activation is Involved in Homing and Engraftment of Hematopoietic Stem Progenitor Cells (HSPCs).

Stem Cell Rev Rep 2020 08;16(4):693-701

Center for Preclinical Studies and Technology, Department of Regenerative Medicine, Medical University of Warsaw, Warsaw, Poland.

Delayed homing and engraftment of hematopoietic stem progenitor cells (HSPCs) or even failure to engraft at all is significant clinical problem after hematopoietic transplant. Therefore, in order to develop more efficient homing and engraftment facilitating strategies it is important to learn more about this process. Our team has postulated that myeloablative conditioning for transplantation induces in bone marrow (BM) microenvironment a state of sterile inflammation in which elements of innate immunity activated by radio- or chemotherapy conditioning for transplant play an important role. In frame with this claim we reported that a significant role in this process plays activation of complement cascade (ComC). Accordingly, mice that that lack a fifth component (C5) of ComC turned out to engraft poorly with normal syngeneic BM cells as compared to normal control animals. In extension of our previous studies we provide for first time evidence that mannan binding lectin (MBL) pathway is involved in activation of ComC in myeloablated transplant recipient BM and thus plays an important role in homing and engraftment of HSPCs. To support this MBL-KO mice show significant defect in hematopoietic reconstitution after hematopoietic transplantation. This correlates with a decrease in expression of stromal derived factor-1 (SDF-1) and impaired activation of Nlrp3 inflammasome in irradiated BM of these mice.
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http://dx.doi.org/10.1007/s12015-020-09983-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392939PMC
August 2020

How to "Detronize" Virus in Crown - Questions to Current Stem Cell Therapies.

Stem Cell Rev Rep 2020 06;16(3):425-426

University of Louisville, Louisville, KY, USA.

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http://dx.doi.org/10.1007/s12015-020-09978-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171434PMC
June 2020

The Nlrp3 inflammasome as a "rising star" in studies of normal and malignant hematopoiesis.

Leukemia 2020 06 20;34(6):1512-1523. Epub 2020 Apr 20.

Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.

Recent investigations indicate that hematopoiesis is coregulated by innate immunity signals and by pathways characteristic of the activation of innate immunity cells that also operate in normal hematopoietic stem progenitor cells (HSPCs). This should not be surprising because of the common developmental origin of these cells from a hemato/lymphopoietic stem cell. An important integrating factor is the Nlrp3 inflammasome, which has emerged as a major sensor of changes in body microenvironments, cell activation, and cell metabolic activity. It is currently the best-studied member of the inflammasome family expressed in hematopoietic and lymphopoietic cells, including also HSPCs. It is proposed as playing a role in (i) the development and expansion of HSPCs, (ii) their release from bone marrow (BM) into peripheral blood (PB) in stress situations and during pharmacological mobilization, (iii) their homing to BM after transplantation, and (iv) their aging and the regulation of hematopoietic cell metabolism. The Nlrp3 inflammasome is also involved in certain hematological pathologies, including (i) myelodysplastic syndrome, (ii) myeloproliferative neoplasms, (iii) leukemia, and (iv) graft-versus-host disease (GvHD) after transplantation. The aim of this review is to shed more light on this intriguing intracellular protein complex that has become a "rising star" in studies focused on both normal steady-state and pathological hematopoiesis.
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http://dx.doi.org/10.1038/s41375-020-0827-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266743PMC
June 2020

Novel Evidence that Purinergic Signaling - Nlrp3 Inflammasome Axis Regulates Circadian Rhythm of Hematopoietic Stem/Progenitor Cells Circulation in Peripheral Blood.

Stem Cell Rev Rep 2020 04;16(2):335-343

Department of Regenerative Medicine, Center for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland.

We found that circadian changes in ATP level in peripheral blood (PB) activate the Nlrp3 inflammasome, which triggers diurnal release of hematopoietic stem/progenitor cells (HSPCs) from murine bone marrow (BM) into PB. Consistent with this finding, we observed circadian changes in expression of mRNA for Nlrp3 inflammasome-related genes, including Nlrp3, caspase 1, IL-1β, IL-18, gasdermin (GSDMD), HMGB1, and S100A9. Circadian release of HSPCs from BM into PB as well as expression of Nlrp3-associated genes was decreased in mice in which pannexin 1-mediated secretion of ATP was inhibited by the blocking peptide 10Panx and in animals exposed to the specific small-molecule inhibitor of the Nlrp3 inflammasome MCC950. In addition to HSPCs, a similar decrease in diurnal cell counts was observed for mesenchymal stromal cells (MSCs), endothelial progenitor cells (EPCs), and very small embryonic-like stem cells (VSELs). These results shed more light on the complexity of circadian regulation of HSPC release into PB, which is coordinated in a purinergic signaling-, innate immunity-dependent manner. Moreover, in addition to circadian changes in expression of the Nlrp3 inflammasome we also observed diurnal changes in expression of other inflammasomes, including Aim2, Nrp1a, and Nlrp1b.
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http://dx.doi.org/10.1007/s12015-020-09953-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7152586PMC
April 2020

Stem Cell Reviews and Reports Enters 16th Year of Publishing.

Stem Cell Rev Rep 2020 Feb;16(1):1-2

University of Louisville, Louisville, KY, USA.

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http://dx.doi.org/10.1007/s12015-019-09951-xDOI Listing
February 2020

Valproic Acid Decreases Endothelial Colony Forming Cells Differentiation and Induces Endothelial-to-Mesenchymal Transition-like Process.

Stem Cell Rev Rep 2020 04;16(2):357-368

Innovative Therapies in Haemostasis, INSERM UMR-S1140, Université de Paris, F-75006, Paris, France.

Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor is a widely used anticonvulsant drug. VPA is also under clinical evaluation to be employed in anticancer therapy, as an antithrombotic agent or a molecule to be used in the stem cells expansion protocols. Since endothelial colony forming cells (ECFC) has been identified as the human postnatal vasculogenic cells involved in thrombotic disorders and serve as a promising source of immature cell for vascular repair, objectives of the present study were to determine how VPA contributes to ECFC commitment and their angiogenic properties. We examined the effect of VPA on ECFC obtained from cord blood by evaluating colony number, proliferation, migration and their sprouting ability in vitro, as well as their in vivo vasculogenic properties. VPA inhibited endothelial differentiation potential from of cord blood derived stem cells associated with decreased proliferation and sprouting activity of cultured ECFC. VPA treatment significantly decreased the vessel-forming ability of ECFC transplanted together with mesenchymal stem cells (MSC) in Matrigel implants in nude mice model. Surprisingly, a microscopic evaluation revealed that VPA induces marked morphological changes from a cobblestone-like EC morphology to enlarged spindle shaped morphology of ECFC. RT-qPCR and a CD31/CD90 flow cytometry analysis confirmed a phenotypic switch of VPA-treated ECFC to mesenchymal-like phenotype. In conclusion, the pan-HDAC inhibitor VPA described for expansion of hematopoietic stem cells and very small embryonic like stem cells cannot be successfully employed for differentiation of endothelial lineage committed ECFC into functional endothelial cells. Our data also suggest that VPA based therapeutics may induce endothelial dysfunction associated with fibrosis that might induce thrombosis recurrence or venous insufficiency.
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http://dx.doi.org/10.1007/s12015-019-09950-yDOI Listing
April 2020

Plausible Links Between Metabolic Networks, Stem Cells, and Longevity.

Adv Exp Med Biol 2019 ;1201:355-388

Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.

Aging is an inevitable consequence of life, and all multicellular organisms undergo a decline in tissue and organ functions as they age. Several well-known risk factors, such as obesity, diabetes, and lack of physical activity that lead to the cardiovascular system, decline and impede the function of vital organs, ultimately limit overall life span. Over recent years, aging research has experienced an unparalleled growth, particularly with the discovery and recognition of genetic pathways and biochemical processes that control to some extent the rate of aging.In this chapter, we focus on several aspects of stem cell biology and aging, beginning with major cellular hallmarks of aging, endocrine regulation of aging and its impact on stem cell compartment, and mechanisms of increased longevity. We then discuss the role of epigenetic modifications associated with aging and provide an overview on a most recent search of antiaging modalities.
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http://dx.doi.org/10.1007/978-3-030-31206-0_15DOI Listing
February 2020

Stem Cells in Psychiatry.

Adv Exp Med Biol 2019 ;1201:159-174

Pomeranian University of Medicine, Szczecin, Poland.

The development of regenerative medicine has provided new perspectives in many scientific fields, including psychiatry. Stem cell research is getting us closer to discovering the biological foundation of mental disorders. In this chapter, we consider the information relating to stem cells and factors involved in their trafficking in peripheral blood in some psychiatric disorders (major depressive disorder, bipolar disorder, schizophrenia, anxiety disorder, and alcohol dependence). The authors also include the implementation of current research regarding neurogenesis in adult brain and induced pluripotent stem cells in investigating concerns in etiopathogenesis of mental disorders as well as the implication of research for treatment of these disorders.
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http://dx.doi.org/10.1007/978-3-030-31206-0_8DOI Listing
February 2020

Hematopoietic Stem and Progenitor Cells (HSPCs).

Adv Exp Med Biol 2019 ;1201:49-77

Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.

Hematopoietic stem/progenitor cells (HSPCs) isolated from bone marrow have been successfully employed for 50 years in hematological transplantations. Currently, these cells are more frequently isolated from mobilized peripheral blood or umbilical cord blood. In this chapter, we overview several topics related to these cells including their phenotype, methods for isolation, and in vitro and in vivo assays to evaluate their proliferative potential. The successful clinical application of HSPCs is widely understood to have helped establish the rationale for the development of stem cell therapies and regenerative medicine.
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http://dx.doi.org/10.1007/978-3-030-31206-0_3DOI Listing
February 2020

Potential Clinical Applications of Stem Cells in Regenerative Medicine.

Adv Exp Med Biol 2019 ;1201:1-22

Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.

The field of regenerative medicine is looking for a pluripotent/multipotent stem cell able to differentiate across germ layers and be safely employed in therapy. Unfortunately, with the exception of hematopoietic stem/progenitor cells (HSPCs) for hematological applications, the current clinical results with stem cells are somewhat disappointing. The potential clinical applications of the more primitive embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have so far been discouraging, as both have exhibited several problems, including genomic instability, a risk of teratoma formation, and the possibility of rejection. Therefore, the only safe stem cells that have so far been employed in regenerative medicine are monopotent stem cells, such as the abovementioned HSPCs or mesenchymal stem cells (MSCs) isolated from postnatal tissues. However, their monopotency, and therefore limited differentiation potential, is a barrier to their broader application in the clinic. Interestingly, results have accumulated indicating that adult tissues contain rare, early-development stem cells known as very small embryonic-like stem cells (VSELs), which can differentiate into cells from more than one germ layer. This chapter addresses different sources of stem cells for potential clinical application and their advantages and problems to be solved.
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http://dx.doi.org/10.1007/978-3-030-31206-0_1DOI Listing
February 2020

Identification of Human Very Small Embryonic like Stem Cells (VSELS) in Human Heart Tissue Among Young and Old Individuals.

Stem Cell Rev Rep 2020 02;16(1):181-185

Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA.

Very Small Embryonic-Like (VSEL) stem cells are a proposed pluripotent population, residing in adult tissues. VSELs have been described in multiple tissues including bone marrow, cord blood, and gonads. They exhibit multiple characteristics of embryonic stem cells including the ability to differentiate into cellular lineages of all three germ layers, including cardiomyocytes and vascular endothelial cells. However, their presence in adult solid organs such as heart in humans has not been established. VSELs are valuable source of stem cells for tissue regeneration and replacement of cells for turnover and usual wear-and-tear. The purpose of our study was to explore the existence of human VSELs (huVSELs) in human heart tissue and examine the changes in their prevalence with aging and cardiac disease. Human heart tissue, collected from healthy and ischemic heart disease subjects was examined for the prevalence of VSELS, defined as CD45-/CD133+/SSEA4+. Both epicardial and endocardial tissues were examined comparing VSEL numbers across different age groups. Our data confirm the existence of huVSELs in adult hearts with decreasing prevalence during aging. This is the first evidence of huVSELs in adult cardiac tissue. Cardiac huVSELs could be further explored in future studies to characterize their primitive potential and therapeutic potential in regenerative studies.
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http://dx.doi.org/10.1007/s12015-019-09923-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027381PMC
February 2020

An Overview of Novel Unconventional Mechanisms of Hematopoietic Development and Regulators of Hematopoiesis - a Roadmap for Future Investigations.

Stem Cell Rev Rep 2019 12;15(6):785-794

Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY, 40202, USA.

Hematopoietic stem cells (HSCs) are the best-characterized stem cells in adult tissues. Nevertheless, as of today, many open questions remain. First, what is the phenotype of the most primitive "pre-HSC" able to undergo asymmetric divisions during ex vivo expansion that gives rise to HSC for all hemato-lymphopoietic lineages. Next, most routine in vitro assays designed to study HSC specification into hematopoietic progenitor cells (HPCs) for major hematopoietic lineages are based on a limited number of peptide-based growth factors and cytokines, neglecting the involvement of several other regulators that are endowed with hematopoietic activity. Examples include many hormones, such as pituitary gonadotropins, gonadal sex hormones, IGF-1, and thyroid hormones, as well as bioactive phosphosphingolipids and extracellular nucleotides (EXNs). Moreover, in addition to regulation by stromal-derived factor 1 (SDF-1), trafficking of these cells during mobilization or homing after transplantation is also regulated by bioactive phosphosphingolipids, EXNs, and three ancient proteolytic cascades, the complement cascade (ComC), the coagulation cascade (CoA), and the fibrinolytic cascade (FibC). Finally, it has emerged that bone marrow responds by "sterile inflammation" to signals sent from damaged organs and tissues, systemic stress, strenuous exercise, gut microbiota, and the administration of certain drugs. This review will address the involvement of these unconventional regulators and present a broader picture of hematopoiesis.
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http://dx.doi.org/10.1007/s12015-019-09920-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925068PMC
December 2019