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Paracrine Effects of Human Stem/Progenitor Cells—From Bench to Bedside

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 38229

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Prof. Dr. Bogusław Machaliński

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Department of Physiopathology, Hematology, and Transplantology, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland
Interests: multiple myeloma research; experimental and clinical hematology; stem cell-based therapies; immunotherapy; angiogenesis; regenerative medicine
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Dear Colleagues,

Various human stem/progenitor cell (SPC) populations have been employed in different experimental models as well as clinical trials aimed at regeneration of damaged tissues, including central nervous system, heart, liver, etc. Despite the potential structural replacement of the impaired cells in some cases, basic and clinical research investigations broadly indicate that SPCs exert a regenerative effect on damaged tissues by paracrine mechanisms. Essentially, a variety of soluble proteins, involving cytokines, chemokines, growth factors, immunologic factors, as well as bioactive lipids, microRNA, and mRNA are released by SPCs and influence the cell–cells crosstalk and the tissue microenvironment. Therefore, these humoral factors play a crucial role in inflammation, angiogenesis, vascular function, and other processes that affect the course of organ self-regeneration. Interestingly, analogous therapeutic effects are sometimes observed after applying different SPC populations, as a consequence of similar paracrine interactions.

We therefore invite investigators to contribute original research as well as review articles that focus on efforts to understand and elucidate different aspects of paracrine mechanisms accompanying human SPCs circulation or adjuvant therapies.

Prof. Dr. Bogusław Machaliński
Guest Editor

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Keywords

stem cell-based adjuvant therapy
trophic effects
tissue regeneration
neuroprotective factors
angiogenesis modulating agents
cytokines
miRNA

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Published Papers (7 papers)

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16 pages, 1809 KiB

Open AccessArticle

Comparative Proteomic Analysis of the Mesenchymal Stem Cells Secretome from Adipose, Bone Marrow, Placenta and Wharton’s Jelly

by Sungho Shin, Jeongmin Lee, Yumi Kwon, Kang-Sik Park, Jae-Hoon Jeong, Suk-Joo Choi, Sa Ik Bang, Jong Wook Chang and Cheolju Lee

Int. J. Mol. Sci. 2021, 22(2), 845; https://doi.org/10.3390/ijms22020845 - 15 Jan 2021

Cited by 115 | Viewed by 8100

Abstract

Mesenchymal stem cells (MSCs) have the potential to be a viable therapy against various diseases due to their paracrine effects, such as secretion of immunomodulatory, trophic and protective factors. These cells are known to be distributed within various organs and tissues. Although they possess the same characteristics, MSCs from different sources are believed to have different secretion potentials and patterns, which may influence their therapeutic effects in disease environments. We characterized the protein secretome of adipose (AD), bone marrow (BM), placenta (PL), and Wharton’s jelly (WJ)-derived human MSCs by using conditioned media and analyzing the secretome by mass spectrometry and follow-up bioinformatics. Each MSC secretome profile had distinct characteristics depending on the source. However, the functional analyses of the secretome from different sources showed that they share similar characteristics, such as cell migration and negative regulation of programmed cell death, even though differences in the composition of the secretome exist. This study shows that the secretome of fetal-derived MSCs, such as PL and WJ, had a more diverse composition than that of AD and BM-derived MSCs, and it was assumed that their therapeutic potential was greater because of these properties. Full article

(This article belongs to the Special Issue Paracrine Effects of Human Stem/Progenitor Cells—From Bench to Bedside)

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24 pages, 3926 KiB

Open AccessArticle

Differential Secretion of Angiopoietic Factors and Expression of MicroRNA in Umbilical Cord Blood from Healthy Appropriate-For-Gestational-Age Preterm and Term Newborns—in Search of Biomarkers of Angiogenesis-Related Processes in Preterm Birth

by Dorota Gródecka-Szwajkiewicz, Zofia Ulańczyk, Edyta Zagrodnik, Karolina Łuczkowska, Dorota Rogińska, Miłosz P. Kawa, Iwona Stecewicz, Krzysztof Safranow and Bogusław Machaliński

Int. J. Mol. Sci. 2020, 21(4), 1305; https://doi.org/10.3390/ijms21041305 - 14 Feb 2020

Cited by 16 | Viewed by 3576

Abstract

Objectives: Premature birth, defined as less than 37 weeks gestation, affects approximately 12% of all live births around the world. Advances in neonatal care have resulted in the increased survival of infants born prematurely. Although prematurity is a known risk factor for different cardiovascular diseases, little is known about the pathophysiology of vasculature during premature gestation and angiopoietic factors network during premature birth. Aims: The objective of this study was to determine whether the profile of several pro-angiogenic and anti-angiogenic factors in umbilical cord blood (UCB) is different in healthy appropriate-for-gestational-age preterm newborns and normal term babies. The second aim of this study was to investigate the microRNA (miRNAs) expression profile in UCB from preterm labor and to detect miRNAs potentially taking part in control of angogenesis-related processes (Angio-MiRs). Methods: Using an immunobead Luminex assay, we simultaneously measured the concentration of Angiogenin, Angiopoietin-1, FGF-acidic, FGF-basic, PDGF-aa, PlGF, VEGF, VEGF-D, Endostatin, Thrombospondin-2, NGF, BDNF, GDNF, and NT-4 in UCB samples collected from the preterm (n = 27) and term (n = 52) delivery. In addition, the global microRNA expression in peripheral blood mononuclear cells (PBMCs) circulating in such UCB samples was examined in this study using microarray MiRNA technique. Results: The concentrations of five from eight measured pro-angiogenic factors (VEGF, Angiopoietin-1, PDGF-AA, FGF-a, and FGF-b) were significantly lower in UCB from preterm newborns. On the contrary, two angiostatic factors (Endostatin and Thrombospondin-2) were significantly up-regulated in preterm UCB. Among analyzed neurotrophins in preterm newborns, the elevated UCB concentration was found only in the case of GDNF, whereas BDNF was significantly reduced. Moreover, two angiopoietic factors, VEGF-D and PlGF, and two neurotrophins, NT4 and NGF, did not differ in concentration in preterm and term babies. We also discovered that among the significantly down-regulated miRNAs, there were several classical Angio-MiRs (inter alia MiR-125, MiR-126, MiR-145, MiR-150, or MiR155), which are involved in angiogenesis regulation in newborn after preterm delivery. Conclusions: This is the first report of simultaneous measurements of several angiopoietic factors in UCB collected from infants during preterm and term labor. Here, we observed that several pro-angiogenic factors were at lower concentration in UCB collected from preterm newborns than term babies. In contrast, the two measured angiostatic factors, Endostatin and Thrombospondin-2, were significantly higher in UCB from preterm babies. This can suggest that distinct pathophysiological contributions from differentially expressed various angiopoietic factors may determine the clinical outcomes after preterm birth. Especially, our angiogenesis-related molecules analysis indicates that preterm birth of healthy, appropriate-for-gestational-age newborns is an “anti-angiogenic state” that may provide an increased risk for improper development and function of cardiovascular system in the adulthood. This work also contributes to a better understanding of the role of miRNAs potentially involved in angiogenesis control in preterm newborns. Full article

(This article belongs to the Special Issue Paracrine Effects of Human Stem/Progenitor Cells—From Bench to Bedside)

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19 pages, 3693 KiB

Open AccessArticle

Local and Systemic Humoral Response to Autologous Lineage-Negative Cells Intrathecal Administration in ALS Patients

by Bartłomiej Baumert, Anna Sobuś, Monika Gołąb-Janowska, Zofia Ulańczyk, Edyta Paczkowska, Karolina Łuczkowska, Alicja Zawiślak, Sławomir Milczarek, Bogumiła Osękowska, Agnieszka Meller, Karolina Machowska-Sempruch, Agnieszka Wełnicka, Krzysztof Safranow, Przemysław Nowacki and Bogusław Machaliński

Int. J. Mol. Sci. 2020, 21(3), 1070; https://doi.org/10.3390/ijms21031070 - 6 Feb 2020

Cited by 12 | Viewed by 3013

Abstract

Amyotrophic lateral sclerosis (ALS) remains a fatal disease with limited therapeutic options. Signaling via neurotrophins (NTs), neuroinflammation, and certain micro-RNAs are believed to play essential role in ALS pathogenesis. Lineage-negative stem/progenitor cells (Lin⁻) were obtained from bone marrow of 18 ALS patients and administered intrathecally. Clinical assessment was performed using ALS Functional Rating Scale (FRSr) and Norris scale. Protein concentrations were measured in plasma and cerebrospinal fluid (CSF) by multiplex fluorescent bead-based immunoassay. Gene expression in nucleated blood cells was assessed using gene microarray technique. Finally, miRNA expression was analyzed using qPCR in CSF and plasma samples. We observed a significant decrease of C-reactive protein (CRP) concentration in plasma on the seventh day from the application of cells. Gene array results revealed decreased expression of gene sets responsible for neutrophil activation. Further analysis revealed moderate negative correlation between CRP level in CSF and clinical outcome. Brain-derived neurotrophic factor (BDNF) concentrations in both plasma and CSF significantly correlated with the favorable clinical outcome. On a micro-RNA level, we observed significant increase of miR-16-5p expression one week after transplantation in both body fluids and significant increase of miR-206 expression in plasma. Administration of Lin⁻ cells may decrease inflammatory response and prevent neurodegeneration. However, these issues require further investigations. Full article

(This article belongs to the Special Issue Paracrine Effects of Human Stem/Progenitor Cells—From Bench to Bedside)

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21 pages, 9663 KiB

Open AccessArticle

Effect of Bortezomib on Global Gene Expression in PC12-Derived Nerve Cells

by Karolina Łuczkowska, Dorota Rogińska, Zofia Ulańczyk and Bogusław Machaliński

Int. J. Mol. Sci. 2020, 21(3), 751; https://doi.org/10.3390/ijms21030751 - 23 Jan 2020

Cited by 12 | Viewed by 3687

Abstract

Peripheral neuropathy is one of the main side-effects of novel therapeutics used in oncohematological diseases, but the molecular basis underlying its development and progression as well as neurotoxicity mechanisms induced by the use of these therapeutics are still not fully elucidated. The aim of this study was to demonstrate the effect of bortezomib on global gene and miRNA expression on PC12-derived nerve cells. Microarray analysis showed that expression of 1383 genes was downregulated at least two fold and 671 genes were upregulated at least two fold in PC12-derived nerve cells treated with bortezomib compared to untreated/control cells. Analysis of functional annotations mainly identified downregulated processes (e.g., regulation of cell cycle, DNA replication and repair, regulation of cell migration, neuron projection morphogenesis and neurotransmitter secretion). The result of miRNA expression analysis demonstrated only 11 significantly downregulated miRNAs (at least two fold) in bortezomib-treated PC12-derived nerve cells vs. control cells. MiRNAs regulate gene expression, therefore we decided to conduct an analysis comparing the outcomes of miRNA microarray expression data to the obtained mRNA data. The most interesting miRNA–target gene correlation is downregulated expression of miR-130a-3p and miR-152-3p and as a result of this downregulation the expression of the Gadd45 increased. This gene is a member of a group of genes, the transcript expression of which is enhanced after stressful growth arrest conditions and treatment with DNA-damaging agents like drugs or mutagens. Full article

(This article belongs to the Special Issue Paracrine Effects of Human Stem/Progenitor Cells—From Bench to Bedside)

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17 pages, 1421 KiB

Open AccessArticle

Associations of MicroRNAs, Angiogenesis-Regulating Factors and CFH Y402H Polymorphism—An Attempt to Search for Systemic Biomarkers in Age-Related Macular Degeneration

by Zofia Ulańczyk, Anna Sobuś, Karolina Łuczkowska, Aleksandra Grabowicz, Katarzyna Mozolewska-Piotrowska, Krzysztof Safranow, Miłosz Piotr Kawa, Andrzej Pałucha, Mariusz Krawczyk, Piotr Sikora, Ewa Matczyńska, Bogusław Machaliński and Anna Machalińska

Int. J. Mol. Sci. 2019, 20(22), 5750; https://doi.org/10.3390/ijms20225750 - 15 Nov 2019

Cited by 14 | Viewed by 2773

Abstract

Age-related macular degeneration (AMD) remains the leading cause of blindness in elderly people, but the pathophysiology of this disease is still largely unknown. We investigated the systemic expression of angiogenesis-regulating growth factors and selected miRNAs known to regulate angiogenesis in AMD patients. We also focused on possible correlations of their expression with the presence of CFH Y402H or ARMS A69S risk variants. A total of 354 AMD patients and 121 controls were enrolled in this study. The levels of angiogenesis-regulating factors were analyzed in plasma samples using Luminex technology. The expression of selected miRNAs was analyzed in peripheral blood plasma using real-time qPCR. The genetic analysis was performed with an Illumina NextSeq500 system. AMD was an independent factor associated with lower levels of angiogenin (β = −0.29, p < 0.001), endostatin (β = −0.18, p < 0.001), FGF-basic (β = −0.18, p < 0.001), PlGF (β = −0.24, p < 0.001), miRNA-21-3p (β = −0.13, p = 0.01) and miRNA-155-5p (β = −0.16, p = 0.002); and with higher levels of FGF-acidic (β = 0.11, p = 0.03), miRNA-23a-3p (β = 0.17, p < 0.001), miRNA-126-5p (β = 0.13, p = 0.009), miRNA-16-5p (β = 0.40, p < 0.001), miRNA-17-3p (β = 0.13, p = 0.01), miRNA-17-5p (β = 0.17, p < 0.001), miRNA-223-3p (β = 0.15, p = 0.004), and miRNA-93 (β = 0.11, p = 0.04). The expression of analyzed miRNA molecules significantly correlated with the levels of tested angiogenesis-regulating factors and clinical parameters in AMD patients, whereas such correlations were not observed in controls. We also found an association between the CFH Y402H polymorphism and miRNA profiles, whereby TT homozygotes showed evidently higher expression of miRNA-16-5p than CC homozygotes or TC heterozygotes (p = 0.0007). Our results suggest that the balance between systemic pro- and anti-angiogenic factors and miRNAs is vital in multifactorial AMD pathogenesis. Full article

(This article belongs to the Special Issue Paracrine Effects of Human Stem/Progenitor Cells—From Bench to Bedside)

19 pages, 975 KiB

Open AccessArticle

Novel Evidence of the Increase in Angiogenic Factor Plasma Levels after Lineage-Negative Stem/Progenitor Cell Intracoronary Infusion in Patients with Acute Myocardial Infarction

by Bartłomiej Baumert, Krzysztof Przybycień, Edyta Paczkowska, Maciej Kotowski, Ewa Pius-Sadowska, Krzysztof Safranow, Jarosław Peregud-Pogorzelski, Zdzisława Kornacewicz-Jach, Małgorzata Peregud-Pogorzelska and Bogusław Machaliński

Int. J. Mol. Sci. 2019, 20(13), 3330; https://doi.org/10.3390/ijms20133330 - 6 Jul 2019

Cited by 7 | Viewed by 2829

Abstract

Cell therapy raises hope to reduce the harmful effects of acute myocardial ischemia. Stem and progenitor cells (SPCs) may be a valuable source of trophic factors. In this study, we assessed the plasma levels of selected trophic factors in patients undergoing application of autologous bone marrow (BM)-derived, lineage-negative (Lin⁻) stem/progenitor cells into the coronary artery in the acute phase of myocardial infarction. The study group consisted of 15 patients with acute myocardial infarction (AMI) who underwent percutaneous revascularization and, afterwards, Lin⁻ stem/progenitor cell administration into the infarct-related artery. The control group consisted of 19 patients. BM Lin⁻ cells were isolated using immunomagnetic methods. Peripheral blood was collected on day 0, 2, 4, and 7 and after the first and third month to assess the concentration of selected trophic factors using multiplex fluorescent bead-based immunoassays. We found in the Lin⁻ group that several angiogenic trophic factors (vascular endothelial growth factor, Angiopoietin-1, basic fibroblast growth factor, platelet-derived growth factor-aa) plasma level significantly increased to the 4th day after myocardial infarction. In parallel, we noticed a tendency where the plasma levels of the brain-derived neurotrophic factor were increased in the Lin^– group. The obtained results suggest that the administered SPCs may be a valuable source of angiogenic trophic factors for damaged myocardium, although this observation requires further in-depth studies. Full article

(This article belongs to the Special Issue Paracrine Effects of Human Stem/Progenitor Cells—From Bench to Bedside)

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Review

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27 pages, 1049 KiB

Open AccessReview

An Update on the Progress of Isolation, Culture, Storage, and Clinical Application of Human Bone Marrow Mesenchymal Stem/Stromal Cells

by Dinh-Toi Chu, Thuy Nguyen Thi Phuong, Nguyen Le Bao Tien, Dang Khoa Tran, Vo Van Thanh, Thuy Luu Quang, Dang Tien Truong, Van Huy Pham, Vo Truong Nhu Ngoc, Thien Chu-Dinh and Kushi Kushekhar

Int. J. Mol. Sci. 2020, 21(3), 708; https://doi.org/10.3390/ijms21030708 - 21 Jan 2020

Cited by 123 | Viewed by 13693

Abstract

Bone marrow mesenchymal stem/stromal cells (BMSCs), which are known as multipotent cells, are widely used in the treatment of various diseases via their self-renewable, differentiation, and immunomodulatory properties. In-vitro and in-vivo studies have supported the understanding mechanisms, safety, and efficacy of BMSCs therapy in clinical applications. The number of clinical trials in phase I/II is accelerating; however, they are limited in the size of subjects, regulations, and standards for the preparation and transportation and administration of BMSCs, leading to inconsistency in the input and outcome of the therapy. Based on the International Society for Cellular Therapy guidelines, the characterization, isolation, cultivation, differentiation, and applications can be optimized and standardized, which are compliant with good manufacturing practice requirements to produce clinical-grade preparation of BMSCs. This review highlights and updates on the progress of production, as well as provides further challenges in the studies of BMSCs, for the approval of BMSCs widely in clinical application. Full article

(This article belongs to the Special Issue Paracrine Effects of Human Stem/Progenitor Cells—From Bench to Bedside)

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