Adipose-Derived Mesenchymal Stem Cells Modulate Fibrosis and Inflammation in the Peritoneal Fibrosis Model Developed in Uremic Rats

Peritoneal fibrosis (PF) represents a long-term complication of peritoneal dialysis (PD), affecting the peritoneal membrane (PM) function. Adipose tissue-derived mesenchymal stem cells (ASC) display immunomodulatory effects and may represent a strategy to block PF. The aim of this study was to analyze the effect of ASC in an experimental PF model developed in uremic rats. To mimic the clinical situation of patients on long-term PD, a combo model, characterized by the combination of PF and chronic kidney disease (CKD), was developed in Wistar rats. Rats were fed with a 0.75% adenine-containing diet, for 30 days, to induce CKD with uremia. PF was induced with intraperitoneal injections of chlorhexidine gluconate (CG) from day 15 to 30. 1×106 ASC were intravenously injected at days 15 and 21. Rats were divided into 5 groups: control, normal rats; CKD, rats receiving adenine diet; PF, rats receiving CG; CKD+PF, CKD rats with PF; CKD+PF+ASC, uremic rats with PF treated with ASC. PF was assessed by Masson trichrome staining. Inflammation- and fibrosis-associated factors were assessed by immunohistochemistry, multiplex analysis, and qPCR. When compared with the control and CKD groups, GC administration induced a striking increase in PM thickness and inflammation in the PF and CKD+PF groups. The development of PF was blocked by ASC treatment. Further, the upregulation of profibrotic factors (TGF-β, fibronectin, and collagen) and the increased myofibroblast expression observed in the CKD+PF group were significantly ameliorated by ASC. Beyond the antifibrotic effect, ASC showed an anti-inflammatory effect avoiding leucocyte infiltration and the overexpression of inflammatory cytokines (IL-1β, TNF-α, and IL-6) in the PM induced by GC. ASC were effective in preventing the development of PF in the experimental model of CKD+PF, probably due to their immunomodulatory properties. These results suggest that ASC may represent a potential strategy for treating long-term PD-associated fibrosis.

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Injectable collagen scaffold promotes swine myocardial infarction recovery by long-term local retention of transplanted human umbilical cord mesenchymal stem cells

Science China Life Sciences ◽

10.1007/s11427-019-1575-x ◽

2020 ◽

Author(s):

Qiang Wang ◽

Xiaojun He ◽

Bin Wang ◽

Jun Pan ◽

Chunying Shi ◽

...

Keyword(s):

Myocardial Infarction ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Umbilical Cord ◽

Collagen Scaffold ◽

Human Umbilical Cord ◽

Injectable Collagen

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Senescence-Associated Secretory Phenotype Suppression Mediated by Small-Sized Mesenchymal Stem Cells Delays Cellular Senescence through TLR2 and TLR5 Signaling

Cells ◽

10.3390/cells10010063 ◽

2021 ◽

Vol 10 (1) ◽

pp. 63

Author(s):

Ji Hye Kwon ◽

Miyeon Kim ◽

Soyoun Um ◽

Hyang Ju Lee ◽

Yun Kyung Bae ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cellular Senescence ◽

Small Cells ◽

Critical Determinant ◽

Senescent Phenotype ◽

Toll Like Receptor 2 ◽

Secretory Phenotype ◽

Major Factors

In order to provide a sufficient number of cells for clinical use, mesenchymal stem cells (MSCs) must be cultured for long-term expansion, which inevitably triggers cellular senescence. Although the small size of MSCs is known as a critical determinant of their fate, the main regulators of stem cell senescence and the underlying signaling have not been addressed. Umbilical cord blood-derived MSCs (UCB-MSCs) were obtained using size-isolation methods and then cultured with control or small cells to investigate the major factors that modulate MSC senescence. Cytokine array data suggested that the secretion of interukin-8 (IL-8) or growth-regulated oncogene-alpha (GROa) by senescent cells was markedly inhibited during incubation of small cells along with suppression of cognate receptor (C-X-C motif chemokine receptor2, CXCR2) via blockade of the autocrine/paracrine positive loop. Moreover, signaling via toll-like receptor 2 (TLR2) and TLR5, both pattern recognition receptors, drove cellular senescence of MSCs, but was inhibited in small cells. The activation of TLRs (2 and 5) through ligand treatment induced a senescent phenotype in small cells. Collectively, our data suggest that small cell from UCB-MSCs exhibit delayed cellular senescence by inhibiting the process of TLR signaling-mediated senescence-associated secretory phenotype (SASP) activation.

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MYOGENIC DIFFERENTIATION OF HUMAN MESENCHYMAL STEM CELLS IN VITRO AND LONG-TERM SURVIVAL IN A NUDE RAT MODEL FOR URINARY INCONTINENCE

The Journal of Urology ◽

10.1016/s0022-5347(09)61907-8 ◽

2009 ◽

Vol 181 (4) ◽

pp. 681

Author(s):

Gerhard Feil ◽

Adriana Drost ◽

Simon Baumann ◽

Jochen Schäfer ◽

Sibylle Weng ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Urinary Incontinence ◽

Rat Model ◽

Myogenic Differentiation ◽

Human Mesenchymal Stem Cells ◽

Term Survival ◽

Nude Rat

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Long-term cultured mesenchymal stem cells frequently develop genomic mutations but do not undergo malignant transformation

Cytotherapy ◽

10.1016/j.jcyt.2014.01.279 ◽

2014 ◽

Vol 16 (4) ◽

pp. S75-S76

Author(s):

Y. Wang ◽

Z. Han ◽

Z. Zhang ◽

Y. Chi ◽

Z. Yang ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Malignant Transformation

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Evaluation of Canine Bone Marrow-derived Mesenchymal Stem Cells After Long-term Cryopreservation

ZOOLOGICAL SCIENCE ◽

10.2108/zsj.30.1032 ◽

2013 ◽

Vol 30 (12) ◽

pp. 1032-1037 ◽

Cited By ~ 10

Author(s):

Xiaofeng Zhu ◽

Fang Yuan ◽

Houxuan Li ◽

Yuqian Zheng ◽

Yin Xiao ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells

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Enhancing therapeutic effects and in vivo tracking of adipose tissue derived mesenchymal stem cells for liver injury using bioorthogonal click chemistry

Nanoscale ◽

10.1039/d0nr07272a ◽

2020 ◽

Author(s):

Naishun Liao ◽

Da Zhang ◽

Ming Wu ◽

Huang-Hao Yang ◽

Xiaolong Liu ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Adipose Tissue ◽

Stem Cell ◽

Liver Injury ◽

Mesenchymal Stem Cell ◽

Liver Diseases ◽

Therapeutic Effects

Adipose tissue derived mesenchymal stem cell (ADSC)-based therapy is attractive for liver diseases, but the long-term therapeutic outcome is still far from satisfaction due to low hepatic engraftment efficiency of...

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DNA Methylation Changes duringIn VitroPropagation of Human Mesenchymal Stem Cells: Implications for Their Genomic Stability?

Stem Cells International ◽

10.1155/2013/192425 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 33

Author(s):

Angela Bentivegna ◽

Mariarosaria Miloso ◽

Gabriele Riva ◽

Dana Foudah ◽

Valentina Butta ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Ex Vivo ◽

Genomic Stability ◽

Great Promise ◽

Human Mscs ◽

Low Oxygen ◽

Long Term Culture ◽

Functional Changes

Mesenchymal stem cells (MSCs) hold great promise for the treatment of numerous diseases. A major problem for MSC therapeutic use is represented by the very low amount of MSCs which can be isolated from different tissues; thusex vivoexpansion is indispensable. Long-term culture, however, is associated with extensive morphological and functional changes of MSCs. In addition, the concern that they may accumulate stochastic mutations which lead the risk of malignant transformation still remains. Overall, the genome of human MSCs (hMSCs) appears to be apparently stable throughout culture, though transient clonal aneuploidies have been detected. Particular attention should be given to the use of low-oxygen environment in order to increase the proliferative capacity of hMSCs, since data on the effect of hypoxic culture conditions on genomic stability are few and contradictory. Furthermore, specific and reproducible epigenetic changes were acquired by hMSCs duringex vivoexpansion, which may be connected and trigger all the biological changes observed. In this review we address current issues on long-term culture of hMSCs with a 360-degree view, starting from the genomic profiles and back, looking for an epigenetic interpretation of their genetic stability.

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Soft Substrate Maintains Proliferative and Adipogenic Differentiation Potential of human Mesenchymal Stem Cells on Long Term Expansion by Delaying Senescence

10.1101/364059 ◽

2018 ◽

Author(s):

Sanjay K. Kureel ◽

Pankaj Mogha ◽

Akshada Khadpekar ◽

Vardhman Kumar ◽

Rohit Joshi ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Culture System ◽

Human Mesenchymal Stem Cells ◽

Population Doubling ◽

Differentiation Potential ◽

Lineage Differentiation ◽

Poly Acrylamide

AbstractHuman mesenchymal stem cells (hMSCs), when cultured on tissue culture plate (TCP) for in vitro expansion, they spontaneously lose their proliferative capacity and multi-lineage differentiation potential. They also lose their distinct spindle morphology and become large and flat. After a certain number of population doubling, they enter into permanent cell cycle arrest, called senescence. This is a major roadblock for clinical use of hMSCs which demands large number of cells. A cell culture system is needed which can maintain the stemness of hMSCs over long term passages yet simple to use. In this study, we explore the role of substrate rigidity in maintaining stemness. hMSCs were serially passaged on TCP and 5 kPa poly-acrylamide gel for 20 population doubling. It was found that while on TCP, cell growth reached a plateau at cumulative population doubling (CPD) = 12.5, on 5 kPa gel, they continue to proliferate linearly till we monitored (CPD = 20). We also found that while on TCP, late passage MSCs lost their adipogenic potential, the same was maintained on soft gel. Cell surface markers related to MSCs were also unaltered. We demonstrated that this maintenance of stemness was correlated with delay in onset of senescence, which was confirmed by β-gal assay and by differential expression of vimentin, Lamin A and Lamin B. As preparation of poly-acrylamide gel is a simple, well established, and well standardized protocol, we believe that this system of cell expansion will be useful in therapeutic and research applications of hMSCs.One Sentence SummaryhMSCs retain their stemness when expanded in vitro on soft polyacrylamide gel coated with collagen by delaying senescence.Significance StatementFor clinical applications, mesenchymal stem cells (MSCs) are required in large numbers. As MSCs are available only in scarcity in vivo, to fulfill the need, extensive in vitro expansion is unavoidable. However, on expansion, they lose their replicative and multi-lineage differentiation potential and become senescent. A culture system that can maintain MSC stemness on long-term expansion, without compromising the stemness, is need of the hour. In this paper, we identified polyacrylamide (PAA) hydrogel of optimum stiffness that can be used to maintain stemness of MSCs during in vitro long term culture. Large quantity of MSCs thus grown can be used in regenerative medicine, cell therapy, and in treatment of inflammatory diseases.

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