International Journal of Molecular Sciences

Editorial

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4 pages, 222 KiB

Open AccessEditorial

Amniotic Fluid and Placental Membranes as Sources of Stem Cells: Progress and Challenges 2.0

by Tullia Maraldi and Valentina Russo

Int. J. Mol. Sci. 2023, 24(22), 16020; https://doi.org/10.3390/ijms242216020 - 7 Nov 2023

Cited by 1 | Viewed by 1407

Abstract

The aim of the second edition of this Special Issue was to collect both review and original research articles that investigate and elucidate the possible therapeutic role of perinatal stem cells in pathological conditions, such as cardiovascular and metabolic diseases, as well as [...] Read more.

The aim of the second edition of this Special Issue was to collect both review and original research articles that investigate and elucidate the possible therapeutic role of perinatal stem cells in pathological conditions, such as cardiovascular and metabolic diseases, as well as inflammatory, autoimmune, musculoskeletal, and degenerative diseases [...] Full article

(This article belongs to the Special Issue Amniotic Fluid and Placental Membranes as Sources of Stem Cells 2.0)

6 pages, 184 KiB

Open AccessEditorial

Amniotic Fluid and Placental Membranes as Sources of Stem Cells: Progress and Challenges

by Tullia Maraldi and Valentina Russo

Int. J. Mol. Sci. 2022, 23(10), 5362; https://doi.org/10.3390/ijms23105362 - 11 May 2022

Cited by 9 | Viewed by 1941

Abstract

The intention of this special edition is to collect review and original research articles that illustrate and stimulate growing efforts to understand the implication of perinatal stem cells in pathological conditions such as cardiovascular and metabolic diseases and inflammatory, autoimmune, musculoskeletal, and degenerative [...] Read more.

The intention of this special edition is to collect review and original research articles that illustrate and stimulate growing efforts to understand the implication of perinatal stem cells in pathological conditions such as cardiovascular and metabolic diseases and inflammatory, autoimmune, musculoskeletal, and degenerative diseases [...] Full article

(This article belongs to the Special Issue Amniotic Fluid and Placental Membranes as Sources of Stem Cells: Progress and Challenges)

Research

Jump to: Editorial, Review

9 pages, 2067 KiB

Open AccessArticle

Non-Permissive Parvovirus B19 Infection: A Reservoir and Questionable Safety Concern in Mesenchymal Stem Cells

by Gloria Bua, Pasquale Marrazzo, Elisabetta Manaresi, Chiara Gamberini, Laura Bonsi, Francesco Alviano and Giorgio Gallinella

Int. J. Mol. Sci. 2023, 24(9), 8204; https://doi.org/10.3390/ijms24098204 - 3 May 2023

Cited by 4 | Viewed by 1852

Abstract

Mesenchymal stromal/stem cells (MSCs) are multipotent cells with differentiation, immunoregulatory and regenerative properties. Because of these features, they represent an attractive tool for regenerative medicine and cell-based therapy. However, MSCs may act as a reservoir of persistent viruses increasing the risk of failure [...] Read more.

Mesenchymal stromal/stem cells (MSCs) are multipotent cells with differentiation, immunoregulatory and regenerative properties. Because of these features, they represent an attractive tool for regenerative medicine and cell-based therapy. However, MSCs may act as a reservoir of persistent viruses increasing the risk of failure of MSCs-based therapies and of viral transmission, especially in immunocompromised patients. Parvovirus B19V (B19V) is a common human pathogen that infects bone marrow erythroid progenitor cells, leading to transient or persistent anemia. Characteristics of B19V include the ability to cross the placenta, infecting the fetus, and to persist in several tissues. We thus isolated MSCs from bone marrow (BM-MSCs) and fetal membrane (FM-MSCs) to investigate their permissiveness to B19V infection. The results suggest that both BM- and FM- MSCs can be infected by B19V and, while not able to support viral replication, allow persistence over time in the infected cultures. Future studies are needed to understand the potential role of MSCs in B19V transmission and the conditions that can favor a potential reactivation of the virus. Full article

(This article belongs to the Special Issue Amniotic Fluid and Placental Membranes as Sources of Stem Cells 2.0)

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20 pages, 2915 KiB

Open AccessArticle

Amniotic Mesenchymal-Derived Extracellular Vesicles and Their Role in the Prevention of Persistent Post-Breeding Induced Endometritis

by Anna Lange-Consiglio, Giulia Gaspari, Federico Funghi, Emanuele Capra, Marina Cretich, Roberto Frigerio, Giampaolo Bosi and Fausto Cremonesi

Int. J. Mol. Sci. 2023, 24(6), 5166; https://doi.org/10.3390/ijms24065166 - 8 Mar 2023

Cited by 4 | Viewed by 1901

Abstract

Persistent post-breeding induced endometritis (PPBIE) is considered a major cause of subfertility in mares. It consists of persistent or delayed uterine inflammation in susceptible mares. There are many options for the treatment of PPBIE, but in this study, a novel approach aimed at [...] Read more.

Persistent post-breeding induced endometritis (PPBIE) is considered a major cause of subfertility in mares. It consists of persistent or delayed uterine inflammation in susceptible mares. There are many options for the treatment of PPBIE, but in this study, a novel approach aimed at preventing the onset of PPBIE was investigated. Stallion semen was supplemented with extracellular vesicles derived from amniotic mesenchymal stromal cells (AMSC-EVs) at the time of insemination to prevent or limit the development of PPBIE. Before use in mares, a dose–response curve was produced to evaluate the effect of AMSC-EVs on spermatozoa, and an optimal concentration of 400 × 10⁶ EVs with 10 × 10⁶ spermatozoa/mL was identified. At this concentration, sperm mobility parameters were not negatively affected. Sixteen susceptible mares were enrolled and inseminated with semen (n = 8; control group) or with semen supplemented with EVs (n = 8; EV group). The supplementation of AMSC-EVs to semen resulted in a reduction in polymorphonuclear neutrophil (PMN) infiltration as well as intrauterine fluid accumulation (IUF; p < 0.05). There was a significant reduction in intrauterine cytokine levels (p < 0.05) for TNF-α and IL-6 and an increase in anti-inflammatory IL-10 in mares in the EV group, suggesting successful modulation of the post-insemination inflammatory response. This procedure may be useful for mares susceptible to PPBIE. Full article

(This article belongs to the Special Issue Amniotic Fluid and Placental Membranes as Sources of Stem Cells 2.0)

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16 pages, 5728 KiB

Open AccessArticle

Effect of 3D Spheroid Culturing on NF-κB Signaling Pathway and Neurogenic Potential in Human Amniotic Fluid Stem Cells

by Giedrė Valiulienė, Aistė Zentelytė, Elizabet Beržanskytė and Rūta Navakauskienė

Int. J. Mol. Sci. 2023, 24(4), 3584; https://doi.org/10.3390/ijms24043584 - 10 Feb 2023

Cited by 2 | Viewed by 1733

Abstract

Human amniotic fluid stem cells (hAFSCs) are known for their advantageous properties when compared to somatic stem cells from other sources. Recently hAFSCs have gained attention for their neurogenic potential and secretory profile. However, hAFSCs in three-dimensional (3D) cultures remain poorly investigated. Therefore, [...] Read more.

Human amniotic fluid stem cells (hAFSCs) are known for their advantageous properties when compared to somatic stem cells from other sources. Recently hAFSCs have gained attention for their neurogenic potential and secretory profile. However, hAFSCs in three-dimensional (3D) cultures remain poorly investigated. Therefore, we aimed to evaluate cellular properties, neural differentiation, and gene and protein expression in 3D spheroid cultures of hAFSCs in comparison to traditional two-dimensional (2D) monolayer cultures. For this purpose, hAFSCs were obtained from amniotic fluid of healthy pregnancies and cultivated in vitro, either in 2D, or 3D under untreated or neuro-differentiated conditions. We observed upregulated expression of pluripotency genes OCT4, NANOG, and MSI1 as well as augmentation in gene expression of NF-κB−TNFα pathway genes (NFKB2, RELA and TNFR2), associated miRNAs (miR103a-5p, miR199a-3p and miR223-3p), and NF-κB p65 protein levels in untreated hAFSC 3D cultures. Additionally, MS analysis of the 3D hAFSCs secretome revealed protein upregulation of IGFs signaling the cascade and downregulation of extracellular matrix proteins, whereas neural differentiation of hAFSC spheroids increased the expression of SOX2, miR223-3p, and MSI1. Summarizing, our study provides novel insights into how 3D culture affects neurogenic potential and signaling pathways of hAFSCs, especially NF-κB, although further studies are needed to elucidate the benefits of 3D cultures more thoroughly. Full article

(This article belongs to the Special Issue Amniotic Fluid and Placental Membranes as Sources of Stem Cells 2.0)

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11 pages, 4599 KiB

Open AccessArticle

Human Amniotic Fluid Stem Cells Ameliorate Thioglycollate-Induced Peritonitis by Increasing Tregs in Mice

by Yushi Abe, Daigo Ochiai, Masako Taguchi, Seiji Kanzaki, Satoru Ikenoue, Yoshifumi Kasuga and Mamoru Tanaka

Int. J. Mol. Sci. 2022, 23(12), 6433; https://doi.org/10.3390/ijms23126433 - 9 Jun 2022

Cited by 3 | Viewed by 2254

Abstract

Mesenchymal stem cells (MSCs) affect immune cells and exert anti-inflammatory effects. Human amniotic fluid stem cells (hAFSCs), a type of MSCs, have a high therapeutic effect in animal models of inflammation-related diseases. hAFSCs can be easily isolated and cultured from amniotic fluid, which [...] Read more.

Mesenchymal stem cells (MSCs) affect immune cells and exert anti-inflammatory effects. Human amniotic fluid stem cells (hAFSCs), a type of MSCs, have a high therapeutic effect in animal models of inflammation-related diseases. hAFSCs can be easily isolated and cultured from amniotic fluid, which is considered a medical waste. Hence, amniotic fluid can be a source of cells for MSC therapy of inflammatory diseases. However, the effect of hAFSCs on acquired immunity in vivo, especially on regulatory T cells, has not yet been fully elucidated. Therefore, in this study, we aimed to understand the effects of hAFSCs on acquired immunity, particularly on regulatory T cells. We showed that hAFSCs ameliorated the thioglycollate-induced inflammation by forming aggregates with host immune cells, such as macrophages, T cells, and B cells in the peritoneal cavity. Further, the regulatory T cells increased in the peritoneal cavity. These results indicated that, in addition to helping the innate immunity, hAFSCs could also aid the acquired immune system in vivo against inflammation-related diseases by increasing regulatory T cells. Full article

(This article belongs to the Special Issue Amniotic Fluid and Placental Membranes as Sources of Stem Cells 2.0)

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14 pages, 3911 KiB

Open AccessArticle

Exosomes Derived from Human Amniotic Fluid Mesenchymal Stem Cells Preserve Microglia and Neuron Cells from Aβ

by Manuela Zavatti, Martina Gatti, Francesca Beretti, Carla Palumbo and Tullia Maraldi

Int. J. Mol. Sci. 2022, 23(9), 4967; https://doi.org/10.3390/ijms23094967 - 29 Apr 2022

Cited by 19 | Viewed by 3903

Abstract

Background: Neuroinflammation is involved in neuronal cell death that occurs in neurodegenerative diseases such as Alzheimer’s disease (AD). Microglia play important roles in regulating the brain amyloid beta (Aβ) levels, so immunomodulatory properties exerted by mesenchymal stem cells may be exploited to treat [...] Read more.

Background: Neuroinflammation is involved in neuronal cell death that occurs in neurodegenerative diseases such as Alzheimer’s disease (AD). Microglia play important roles in regulating the brain amyloid beta (Aβ) levels, so immunomodulatory properties exerted by mesenchymal stem cells may be exploited to treat this pathology. The evidence suggests that the mechanism of action of human amniotic fluid stem cells (hAFSCs) is through their secretome, which includes exosomes (exo). Methods: We examined the effect of exosomes derived from human amniotic fluid stem cells (hAFSCs-exo) on activated BV-2 microglia cells by lipopolysaccharide (LPS) as a neuroinflammation model. To investigate the exo effect on the interplay between AD neurons and microglia, SH-SY5Y neuroblastoma cells treated with Aβ were exposed to a conditioned medium (CM) obtained from activated BV-2 or co-culture systems. Results: We found that the upregulation of the markers of pro-inflammatory microglia was prevented when exposed to hAFSC-exo whereas the markers of the anti-inflammatory macrophage phenotype were not affected. Interestingly, the hAFSC-exo pretreatment significantly inhibited the oxidative stress rise and apoptosis occurring in the neurons in presence of both microglia and Aβ. Conclusion: We demonstrated that hAFSC-exo mitigated an inflammatory injury caused by microglia and significantly recovered the neurotoxicity, suggesting that hAFSC-exo may be a potential therapeutic agent for inflammation-related neurological conditions, including AD. Full article

(This article belongs to the Special Issue Amniotic Fluid and Placental Membranes as Sources of Stem Cells 2.0)

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15 pages, 2756 KiB

Open AccessArticle

Changes in the Transcriptome Profiles of Human Amnion-Derived Mesenchymal Stromal/Stem Cells Induced by Three-Dimensional Culture: A Potential Priming Strategy to Improve Their Properties

by Alessia Gallo, Nicola Cuscino, Flavia Contino, Matteo Bulati, Mariangela Pampalone, Giandomenico Amico, Giovanni Zito, Claudia Carcione, Claudio Centi, Alessandro Bertani, Pier Giulio Conaldi and Vitale Miceli

Int. J. Mol. Sci. 2022, 23(2), 863; https://doi.org/10.3390/ijms23020863 - 13 Jan 2022

Cited by 17 | Viewed by 2509

Abstract

Mesenchymal stromal/stem cells (MSCs) are believed to function in vivo as a homeostatic tool that shows therapeutic properties for tissue repair/regeneration. Conventionally, these cells are expanded in two-dimensional (2D) cultures, and, in that case, MSCs undergo genotypic/phenotypic changes resulting in a loss of [...] Read more.

Mesenchymal stromal/stem cells (MSCs) are believed to function in vivo as a homeostatic tool that shows therapeutic properties for tissue repair/regeneration. Conventionally, these cells are expanded in two-dimensional (2D) cultures, and, in that case, MSCs undergo genotypic/phenotypic changes resulting in a loss of their therapeutic capabilities. Moreover, several clinical trials using MSCs have shown controversial results with moderate/insufficient therapeutic responses. Different priming methods were tested to improve MSC effects, and three-dimensional (3D) culturing techniques were also examined. MSC spheroids display increased therapeutic properties, and, in this context, it is crucial to understand molecular changes underlying spheroid generation. To address these limitations, we performed RNA-seq on human amnion-derived MSCs (hAMSCs) cultured in both 2D and 3D conditions and examined the transcriptome changes associated with hAMSC spheroid formation. We found a large number of 3D culture-sensitive genes and identified selected genes related to 3D hAMSC therapeutic effects. In particular, we observed that these genes can regulate proliferation/differentiation, as well as immunomodulatory and angiogenic processes. We validated RNA-seq results by qRT-PCR and methylome analysis and investigation of secreted factors. Overall, our results showed that hAMSC spheroid culture represents a promising approach to cell-based therapy that could significantly impact hAMSC application in the field of regenerative medicine. Full article

(This article belongs to the Special Issue Amniotic Fluid and Placental Membranes as Sources of Stem Cells 2.0)

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32 pages, 6655 KiB

Open AccessArticle

Comprehensive Profiling of Secretome Formulations from Fetal- and Perinatal Human Amniotic Fluid Stem Cells

by Ambra Costa, Davide Ceresa, Antonella De Palma, Rossana Rossi, Sara Turturo, Sara Santamaria, Carolina Balbi, Federico Villa, Daniele Reverberi, Katia Cortese, Pierangela De Biasio, Dario Paladini, Domenico Coviello, Silvia Ravera, Paolo Malatesta, Pierluigi Mauri, Rodolfo Quarto and Sveva Bollini

Int. J. Mol. Sci. 2021, 22(7), 3713; https://doi.org/10.3390/ijms22073713 - 2 Apr 2021

Cited by 17 | Viewed by 4566

Abstract

We previously reported that c-KIT+ human amniotic-fluid derived stem cells obtained from leftover samples of routine II trimester prenatal diagnosis (fetal hAFS) are endowed with regenerative paracrine potential driving pro-survival, anti-fibrotic and proliferative effects. hAFS may also be isolated from III trimester clinical [...] Read more.

We previously reported that c-KIT+ human amniotic-fluid derived stem cells obtained from leftover samples of routine II trimester prenatal diagnosis (fetal hAFS) are endowed with regenerative paracrine potential driving pro-survival, anti-fibrotic and proliferative effects. hAFS may also be isolated from III trimester clinical waste samples during scheduled C-sections (perinatal hAFS), thus offering a more easily accessible alternative when compared to fetal hAFS. Nonetheless, little is known about the paracrine profile of perinatal hAFS. Here we provide a detailed characterization of the hAFS total secretome (i.e., the entirety of soluble paracrine factors released by cells in the conditioned medium, hAFS-CM) and the extracellular vesicles (hAFS-EVs) within it, from II trimester fetal- versus III trimester perinatal cells. Fetal- and perinatal hAFS were characterized and subject to hypoxic preconditioning to enhance their paracrine potential. hAFS-CM and hAFS-EV formulations were analyzed for protein and chemokine/cytokine content, and the EV cargo was further investigated by RNA sequencing. The phenotype of fetal- and perinatal hAFS, along with their corresponding secretome formulations, overlapped; yet, fetal hAFS showed immature oxidative phosphorylation activity when compared to perinatal ones. The profiling of their paracrine cargo revealed some differences according to gestational stage and hypoxic preconditioning. Both cell sources provided formulations enriched with neurotrophic, immunomodulatory, anti-fibrotic and endothelial stimulating factors, and the immature fetal hAFS secretome was defined by a more pronounced pro-vasculogenic, regenerative, pro-resolving and anti-aging profile. Small RNA profiling showed microRNA enrichment in both fetal- and perinatal hAFS-EV cargo, with a stably- expressed pro-resolving core as a reference molecular signature. Here we confirm that hAFS represents an appealing source of regenerative paracrine factors; the selection of either fetal or perinatal hAFS secretome formulations for future paracrine therapy should be evaluated considering the specific clinical scenario. Full article

(This article belongs to the Special Issue Amniotic Fluid and Placental Membranes as Sources of Stem Cells: Progress and Challenges)

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19 pages, 6052 KiB

Open AccessArticle

Conditioned Medium from Human Amnion-Derived Mesenchymal Stromal/Stem Cells Attenuating the Effects of Cold Ischemia-Reperfusion Injury in an In Vitro Model Using Human Alveolar Epithelial Cells

by Vitale Miceli, Alessandro Bertani, Cinzia Maria Chinnici, Matteo Bulati, Mariangela Pampalone, Giandomenico Amico, Claudia Carcione, Eva Schmelzer, Jörg C. Gerlach and Pier Giulio Conaldi

Int. J. Mol. Sci. 2021, 22(2), 510; https://doi.org/10.3390/ijms22020510 - 6 Jan 2021

Cited by 23 | Viewed by 3045

Abstract

The clinical results of lung transplantation (LTx) are still less favorable than other solid organ transplants in both the early and long term. The fragility of the lungs limits the procurement rate and can favor the occurrence of ischemia-reperfusion injury (IRI). Ex vivo [...] Read more.

The clinical results of lung transplantation (LTx) are still less favorable than other solid organ transplants in both the early and long term. The fragility of the lungs limits the procurement rate and can favor the occurrence of ischemia-reperfusion injury (IRI). Ex vivo lung perfusion (EVLP) with Steen Solution^TM (SS) aims to address problems, and the implementation of EVLP to alleviate the activation of IRI-mediated processes has been achieved using mesenchymal stromal/stem cell (MSC)-based treatments. In this study, we investigated the paracrine effects of human amnion-derived MSCs (hAMSCs) in an in vitro model of lung IRI that includes cold ischemia and normothermic EVLP. We found that SS enriched by a hAMSC-conditioned medium (hAMSC-CM) preserved the viability and delayed the apoptosis of alveolar epithelial cells (A549) through the downregulation of inflammatory factors and the upregulation of antiapoptotic factors. These effects were more evident using the CM of 3D hAMSC cultures, which contained an increased amount of immunosuppressive and growth factors compared to both 2D cultures and encapsulated-hAMSCs. To conclude, we demonstrated an in vitro model of lung IRI and provided evidence that a hAMSC-CM attenuated IRI effects by improving the efficacy of EVLP, leading to strategies for a potential implementation of this technique. Full article

(This article belongs to the Special Issue Amniotic Fluid and Placental Membranes as Sources of Stem Cells: Progress and Challenges)

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17 pages, 2479 KiB

Open AccessArticle

Amniotic Fluid Stem Cell-Derived Extracellular Vesicles Counteract Steroid-Induced Osteoporosis In Vitro

by Martina Gatti, Francesca Beretti, Manuela Zavatti, Emma Bertucci, Soraia Ribeiro Luz, Carla Palumbo and Tullia Maraldi

Int. J. Mol. Sci. 2021, 22(1), 38; https://doi.org/10.3390/ijms22010038 - 22 Dec 2020

Cited by 24 | Viewed by 2882

Abstract

Background—Osteoporosis is characterized by defects in both quality and quantity of bone tissue, which imply high susceptibility to fractures with limitations of autonomy. Current therapies for osteoporosis are mostly concentrated on how to inhibit bone resorption but give serious adverse effects. Therefore, more [...] Read more.

Background—Osteoporosis is characterized by defects in both quality and quantity of bone tissue, which imply high susceptibility to fractures with limitations of autonomy. Current therapies for osteoporosis are mostly concentrated on how to inhibit bone resorption but give serious adverse effects. Therefore, more effective and safer therapies are needed that even encourage bone formation. Here we examined the effect of extracellular vesicles secreted by human amniotic fluid stem cells (AFSC) (AFSC-EV) on a model of osteoporosis in vitro. Methods—human AFSC-EV were added to the culture medium of a human pre-osteoblast cell line (HOB) induced to differentiate, and then treated with dexamethasone as osteoporosis inducer. Aspects of differentiation and viability were assessed by immunofluorescence, Western blot, mass spectrometry, and histological assays. Since steroids induce oxidative stress, the levels of reactive oxygen species and of redox related proteins were evaluated. Results—AFSC-EV were able to ameliorate the differentiation ability of HOB both in the case of pre-osteoblasts and when the differentiation process was affected by dexamethasone. Moreover, the viability was increased and parallelly apoptotic markers were reduced. The presence of EV positively modulated the redox unbalance due to dexamethasone. Conclusion—these findings demonstrated that EV from hAFSC have the ability to recover precursor cell potential and delay local bone loss in steroid-related osteoporosis. Full article

(This article belongs to the Special Issue Amniotic Fluid and Placental Membranes as Sources of Stem Cells: Progress and Challenges)

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12 pages, 2160 KiB

Open AccessArticle

Prophylactic Therapy with Human Amniotic Fluid Stem Cells Improves Long-Term Cognitive Impairment in Rat Neonatal Sepsis Survivors

by Yushi Abe, Daigo Ochiai, Yu Sato, Seiji Kanzaki, Satoru Ikenoue, Yoshifumi Kasuga and Mamoru Tanaka

Int. J. Mol. Sci. 2020, 21(24), 9590; https://doi.org/10.3390/ijms21249590 - 16 Dec 2020

Cited by 9 | Viewed by 2333

Abstract

A systemic inflammatory response induces multiple organ dysfunction and results in poor long-term neurological outcomes in neonatal sepsis. However, there is no effective therapy for treating or preventing neonatal sepsis besides antibiotics and supportive care. Therefore, a novel strategy to improve neonatal sepsis-related [...] Read more.

A systemic inflammatory response induces multiple organ dysfunction and results in poor long-term neurological outcomes in neonatal sepsis. However, there is no effective therapy for treating or preventing neonatal sepsis besides antibiotics and supportive care. Therefore, a novel strategy to improve neonatal sepsis-related morbidity and mortality is desirable. Recently, we reported that prophylactic therapy with human amniotic stem cells (hAFSCs) improved survival in a rat model of lipopolysaccharide (LPS)-induced neonatal sepsis through immunomodulation. Besides improving the mortality, increasing survival without major morbidities is an important goal of neonatal intensive care for neonatal sepsis. This study investigated long-term neurological outcomes in neonatal sepsis survivors treated with hAFSCs using the LPS-induced neonatal sepsis model in rats. We found that prophylactic therapy with hAFSCs improved spatial awareness and memory-based behavior in neonatal sepsis survivors at adolescence in rats. The treatment suppressed acute reactive gliosis and subsequently reduced astrogliosis in the hippocampal region over a long period of assessment. To the best of our knowledge, this is the first report that proves the concept that hAFSC treatment improves cognitive impairment in neonatal sepsis survivors. We demonstrate the efficacy of hAFSC therapy in improving the mortality and morbidity associated with neonatal sepsis. Full article

(This article belongs to the Special Issue Amniotic Fluid and Placental Membranes as Sources of Stem Cells: Progress and Challenges)

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20 pages, 6674 KiB

Open AccessArticle

The Effect of Angiotensin II, Retinoic Acid, EGCG, and Vitamin C on the Cardiomyogenic Differentiation Induction of Human Amniotic Fluid-Derived Mesenchymal Stem Cells

by Monika Gasiūnienė, Elvina Valatkaitė, Aistė Navakauskaitė and Rūta Navakauskienė

Int. J. Mol. Sci. 2020, 21(22), 8752; https://doi.org/10.3390/ijms21228752 - 19 Nov 2020

Cited by 7 | Viewed by 2499

Abstract

Human amniotic fluid-derived mesenchymal stem cells (AF-MSCs) may be potentially applied in cell therapy or regenerative medicine as a new alternative source of stem cells. They could be particularly valuable in restoring cardiac tissue after myocardial infarction or other cardiovascular diseases. We investigated [...] Read more.

Human amniotic fluid-derived mesenchymal stem cells (AF-MSCs) may be potentially applied in cell therapy or regenerative medicine as a new alternative source of stem cells. They could be particularly valuable in restoring cardiac tissue after myocardial infarction or other cardiovascular diseases. We investigated the potential of biologically active compounds, namely, angiotensin II, retinoic acid (RA), epigallocatechin-3-gallate (EGCG), vitamin C alone, and the combinations of RA, EGCG, and vitamin C with angiotensin II to induce cardiomyogenic differentiation of AF-MSCs. We observed that the upregulated expression of cardiac gene markers (NKX2-5, MYH6, TNNT2, and DES) and cardiac ion channel genes (sodium, calcium, the potassium) as well as the increased levels of Connexin 43 and Nkx2.5 proteins. Extracellular flux analysis, applied for the first time on AF-MSCs induced with biologically active compounds, revealed the switch in AF-MSCs energetic phenotype and enhanced utilization of oxidative phosphorylation for energy production. Moreover, we demonstrated changes in epigenetic marks associated with transcriptionally active (H3K4me3, H3K9ac, and H4hyperAc) or repressed (H3K27me3) chromatin. All in all, we demonstrated that explored biomolecules were able to induce alterations in AF-MSCs at the phenotypic, genetic, protein, metabolic, and epigenetic levels, leading to the formation of cardiomyocyte progenitors that may become functional heart cells in vitro or in vivo. Full article

(This article belongs to the Special Issue Amniotic Fluid and Placental Membranes as Sources of Stem Cells: Progress and Challenges)

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16 pages, 4473 KiB

Open AccessArticle

Human Mesenchymal Stromal Cells Unveil an Unexpected Differentiation Potential toward the Dopaminergic Neuronal Lineage

by Giulia Gaggi, Andrea Di Credico, Pascal Izzicupo, Francesco Alviano, Michele Di Mauro, Angela Di Baldassarre and Barbara Ghinassi

Int. J. Mol. Sci. 2020, 21(18), 6589; https://doi.org/10.3390/ijms21186589 - 9 Sep 2020

Cited by 13 | Viewed by 3280

Abstract

Degeneration of dopaminergic neurons represents the cause of many neurodegenerative diseases, with increasing incidence worldwide. The replacement of dead cells with new healthy ones may represent an appealing therapeutic approach to these pathologies, but currently, only pluripotent stem cells can generate dopaminergic neurons [...] Read more.

Degeneration of dopaminergic neurons represents the cause of many neurodegenerative diseases, with increasing incidence worldwide. The replacement of dead cells with new healthy ones may represent an appealing therapeutic approach to these pathologies, but currently, only pluripotent stem cells can generate dopaminergic neurons with high efficiency. However, with the use of these cells arises safety and/or ethical issues. Human mesenchymal stromal cells (hFM-MSCs) are perinatal stem cells that can be easily isolated from the amniochorionic membrane after delivery. Generally considered multipotent, their real differentiative potential is not completely elucidated. The aim of this study was to analyze their stemness characteristics and to evaluate whether they may overcome their mesenchymal fate, generating dopaminergic neurons. We demonstrated that hFM-MSCs expressed embryonal genes OCT4, NANOG, SOX2, KLF4, OVOL1, and ESG1, suggesting they have some features of pluripotency. Moreover, hFM-MSCs that underwent a dopaminergic differentiation protocol gradually increased the transcription of dopaminergic markers LMX1b, NURR1, PITX3, and DAT. We finally obtained a homogeneous population of cells resembling the morphology of primary midbrain dopaminergic neurons that expressed the functional dopaminergic markers TH, DAT, and Nurr1. In conclusion, our results suggested that hFM-MSCs retain the expression of pluripotency genes and are able to differentiate not only into mesodermal cells, but also into neuroectodermal dopaminergic neuron-like cells. Full article

(This article belongs to the Special Issue Amniotic Fluid and Placental Membranes as Sources of Stem Cells: Progress and Challenges)

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19 pages, 7048 KiB

Open AccessArticle

Dose-Response Tendon-Specific Markers Induction by Growth Differentiation Factor-5 in Human Bone Marrow and Umbilical Cord Mesenchymal Stem Cells

by Maria Camilla Ciardulli, Luigi Marino, Erwin Pavel Lamparelli, Maurizio Guida, Nicholas Robert Forsyth, Carmine Selleri, Giovanna Della Porta and Nicola Maffulli

Int. J. Mol. Sci. 2020, 21(16), 5905; https://doi.org/10.3390/ijms21165905 - 17 Aug 2020

Cited by 25 | Viewed by 4369

Abstract

Mesenchymal stem cells derived from human bone marrow (hBM-MSCs) are utilized in tendon tissue-engineering protocols while extra-embryonic cord-derived, including from Wharton’s Jelly (hWJ-MSCs), are emerging as useful alternatives. To explore the tenogenic responsiveness of hBM-MSCs and hWJ-MSCs to human Growth Differentiation Factor 5 [...] Read more.

Mesenchymal stem cells derived from human bone marrow (hBM-MSCs) are utilized in tendon tissue-engineering protocols while extra-embryonic cord-derived, including from Wharton’s Jelly (hWJ-MSCs), are emerging as useful alternatives. To explore the tenogenic responsiveness of hBM-MSCs and hWJ-MSCs to human Growth Differentiation Factor 5 (hGDF-5) we supplemented each at doses of 1, 10, and 100 ng/mL of hGDF-5 and determined proliferation, morphology and time-dependent expression of tenogenic markers. We evaluated the expression of collagen types 1 (COL1A1) and 3 (COL3A1), Decorin (DCN), Scleraxis-A (SCX-A), Tenascin-C (TNC) and Tenomodulin (TNMD) noting the earliest and largest increase with 100 ng/mL. With 100 ng/mL, hBM-MSCs showed up-regulation of SCX-A (1.7-fold) at Day 1, TNC (1.3-fold) and TNMD (12-fold) at Day 8. hWJ-MSCs, at the same dose, showed up-regulation of COL1A1 (3-fold), DCN (2.7-fold), SCX-A (3.8-fold) and TNC (2.3-fold) after three days of culture. hWJ-MSCs also showed larger proliferation rate and marked aggregation into a tubular-shaped system at Day 7 (with 100 ng/mL of hGDF-5). Simultaneous to this, we explored the expression of pro-inflammatory (IL-6, TNF, IL-12A, IL-1β) and anti-inflammatory (IL-10, TGF-β1) cytokines across for both cell types. hBM-MSCs exhibited a better balance of pro-inflammatory and anti-inflammatory cytokines up-regulating IL-1β (11-fold) and IL-10 (10-fold) at Day 8; hWJ-MSCs, had a slight expression of IL-12A (1.5-fold), but a greater up-regulation of IL-10 (2.5-fold). Type 1 collagen and tenomodulin proteins, detected by immunofluorescence, confirming the greater protein expression when 100 ng/mL were supplemented. In the same conditions, both cell types showed specific alignment and shape modification with a length/width ratio increase, suggesting their response in activating tenogenic commitment events, and they both potential use in 3D in vitro tissue-engineering protocols. Full article

(This article belongs to the Special Issue Amniotic Fluid and Placental Membranes as Sources of Stem Cells: Progress and Challenges)

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31 pages, 2400 KiB

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Characteristics and Therapeutic Potential of Human Amnion-Derived Stem Cells

by Quan-Wen Liu, Qi-Ming Huang, Han-You Wu, Guo-Si-Lang Zuo, Hao-Cheng Gu, Ke-Yu Deng and Hong-Bo Xin

Int. J. Mol. Sci. 2021, 22(2), 970; https://doi.org/10.3390/ijms22020970 - 19 Jan 2021

Cited by 72 | Viewed by 10101

Abstract

Stem cells including embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and adult stem cells (ASCs) are able to repair/replace damaged or degenerative tissues and improve functional recovery in experimental model and clinical trials. However, there are still many limitations and unresolved [...] Read more.

Stem cells including embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and adult stem cells (ASCs) are able to repair/replace damaged or degenerative tissues and improve functional recovery in experimental model and clinical trials. However, there are still many limitations and unresolved problems regarding stem cell therapy in terms of ethical barriers, immune rejection, tumorigenicity, and cell sources. By reviewing recent literatures and our related works, human amnion-derived stem cells (hADSCs) including human amniotic mesenchymal stem cells (hAMSCs) and human amniotic epithelial stem cells (hAESCs) have shown considerable advantages over other stem cells. In this review, we first described the biological characteristics and advantages of hADSCs, especially for their high pluripotency and immunomodulatory effects. Then, we summarized the therapeutic applications and recent progresses of hADSCs in treating various diseases for preclinical research and clinical trials. In addition, the possible mechanisms and the challenges of hADSCs applications have been also discussed. Finally, we highlighted the properties of hADSCs as a promising source of stem cells for cell therapy and regenerative medicine and pointed out the perspectives for the directions of hADSCs applications clinically. Full article

(This article belongs to the Special Issue Amniotic Fluid and Placental Membranes as Sources of Stem Cells: Progress and Challenges)

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12 pages, 792 KiB

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Progress and Challenges of Amniotic Fluid Derived Stem Cells in Therapy of Ischemic Heart Disease

by Yi-Hsien Fang, Saprina P. H. Wang, Hsien-Yuan Chang, Pei-Jung Yang, Ping-Yen Liu and Yen-Wen Liu

Int. J. Mol. Sci. 2021, 22(1), 102; https://doi.org/10.3390/ijms22010102 - 24 Dec 2020

Cited by 6 | Viewed by 5304

Abstract

Cardiovascular disease is the leading cause of deaths worldwide, claiming an estimated total of 17.9 million lives each year, of which one-third of the people are under the age of 70 years. Since adult cardiomyocytes fail to regenerate, the heart loses the ability [...] Read more.

Cardiovascular disease is the leading cause of deaths worldwide, claiming an estimated total of 17.9 million lives each year, of which one-third of the people are under the age of 70 years. Since adult cardiomyocytes fail to regenerate, the heart loses the ability to repair itself after an injury, making patients with heart disease suffer from poor prognosis. Pluripotent stem cells have the ability to differentiate into cardiomyocytes in vitro through a well-established process, which is a new advancement in cardiac regeneration therapy. However, pluripotent stem cell-derived cardiomyocytes have certain drawbacks, such as the risk of arrhythmia and immune incompatibility. Thus, amniotic fluid stem cells (AFSCs), a relatively novel source of stem cells, have been exploited for their ability of pluripotent differentiation. In addition, since AFSCs are weakly positive for the major histocompatibility class II molecules, they may have high immune tolerance. In summary, the possibility of development of cardiomyocytes from AFSCs, as well as their transplantation in host cells to produce mechanical contraction, has been discussed. Thus, this review article highlights the progress of AFSC therapy and its application in the treatment of heart diseases in recent years. Full article

(This article belongs to the Special Issue Amniotic Fluid and Placental Membranes as Sources of Stem Cells: Progress and Challenges)

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26 pages, 321 KiB

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Human Amniotic Epithelial Stem Cells: A Promising Seed Cell for Clinical Applications

by Chen Qiu, Zhen Ge, Wenyu Cui, Luyang Yu and Jinying Li

Int. J. Mol. Sci. 2020, 21(20), 7730; https://doi.org/10.3390/ijms21207730 - 19 Oct 2020

Cited by 47 | Viewed by 4966

Abstract

Perinatal stem cells have been regarded as an attractive and available cell source for medical research and clinical trials in recent years. Multiple stem cell types have been identified in the human placenta. Recent advances in knowledge on placental stem cells have revealed [...] Read more.

Perinatal stem cells have been regarded as an attractive and available cell source for medical research and clinical trials in recent years. Multiple stem cell types have been identified in the human placenta. Recent advances in knowledge on placental stem cells have revealed that human amniotic epithelial stem cells (hAESCs) have obvious advantages and can be used as a novel potential cell source for cellular therapy and clinical application. hAESCs are known to possess stem-cell-like plasticity, immune-privilege, and paracrine properties. In addition, non-tumorigenicity and a lack of ethical concerns are two major advantages compared with embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). All of the characteristics mentioned above and other additional advantages, including easy accessibility and a non-invasive application procedure, make hAESCs a potential ideal cell type for use in both research and regenerative medicine in the near future. This review article summarizes current knowledge on the characteristics, therapeutic potential, clinical advances and future challenges of hAESCs in detail. Full article

(This article belongs to the Special Issue Amniotic Fluid and Placental Membranes as Sources of Stem Cells: Progress and Challenges)

78 pages, 3990 KiB

Open AccessReview

In Vitro Innovation of Tendon Tissue Engineering Strategies

by Maria Rita Citeroni, Maria Camilla Ciardulli, Valentina Russo, Giovanna Della Porta, Annunziata Mauro, Mohammad El Khatib, Miriam Di Mattia, Devis Galesso, Carlo Barbera, Nicholas R. Forsyth, Nicola Maffulli and Barbara Barboni

Int. J. Mol. Sci. 2020, 21(18), 6726; https://doi.org/10.3390/ijms21186726 - 14 Sep 2020

Cited by 50 | Viewed by 8587

Abstract

Tendinopathy is the term used to refer to tendon disorders. Spontaneous adult tendon healing results in scar tissue formation and fibrosis with suboptimal biomechanical properties, often resulting in poor and painful mobility. The biomechanical properties of the tissue are negatively affected. Adult tendons [...] Read more.

Tendinopathy is the term used to refer to tendon disorders. Spontaneous adult tendon healing results in scar tissue formation and fibrosis with suboptimal biomechanical properties, often resulting in poor and painful mobility. The biomechanical properties of the tissue are negatively affected. Adult tendons have a limited natural healing capacity, and often respond poorly to current treatments that frequently are focused on exercise, drug delivery, and surgical procedures. Therefore, it is of great importance to identify key molecular and cellular processes involved in the progression of tendinopathies to develop effective therapeutic strategies and drive the tissue toward regeneration. To treat tendon diseases and support tendon regeneration, cell-based therapy as well as tissue engineering approaches are considered options, though none can yet be considered conclusive in their reproduction of a safe and successful long-term solution for full microarchitecture and biomechanical tissue recovery. In vitro differentiation techniques are not yet fully validated. This review aims to compare different available tendon in vitro differentiation strategies to clarify the state of art regarding the differentiation process. Full article

(This article belongs to the Special Issue Amniotic Fluid and Placental Membranes as Sources of Stem Cells: Progress and Challenges)

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