The Human Amnion Epithelial Cell Secretome Decreases Hepatic Fibrosis in Mice with Chronic Liver Fibrosis

Alhomrani, Majid; Correia, Jeanne; Zavou, Marcus James; Leaw, Bryan; Kuk, Nathan; Xu, Rong; Saad, Mohamed I.; Hodge, Alexander; Greening, David W.; Lim, Rebecca; Sievert, William

doi:10.3389/fphar.2017.00748

Cited by 71 publications

(108 citation statements)

References 75 publications

(95 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Proteomic analysis of hAEC‐CM by Alhomarani et al . identified over 160 different proteins that can influence cellular communication and physiological processes . The hAEC secrotome may also affect molecules such as TGF‐β1 and MMP‐9 that can shift the dynamic equilibrium between ECM deposition and degradation.…”

Section: Discussionmentioning

confidence: 99%

Human amnion epithelial cells and their soluble factors reduce liver fibrosis in murine non‐alcoholic steatohepatitis

Kuk

Hodge

Sun

et al. 2019

J of Gastro and Hepatol

Self Cite

View full text Add to dashboard Cite

Background and Aim Non‐alcoholic steatohepatitis (NASH) can lead to cirrhosis and hepatocellular carcinoma. Currently, lifestyle modification is the only effective treatment. We have shown that human amnion epithelial cells (hAECs) reduce inflammation and fibrosis in toxin‐induced liver injury models. We examined the effect of these cells and the soluble factors released by the cells into culture medium (hAEC conditioned medium [hAEC‐CM]) in a diet‐induced murine NASH model. Methods C57BL/6J male mice received a Western “fast food diet” for 42 weeks. Group 1 received an intraperitoneal injection of 2 × 106 hAECs at week 34, group 2 received an additional hAEC dose at week 38, and group 3 received thrice weekly hAEC‐CM injections intraperitoneal for 8 weeks from week 34. Liver fibrosis area, inflammation, and fibrosis regulators were measured by immunohistochemistry, qPCR, and gelatin zymography. Metabolic parameters were also assessed. Results Fast food diet‐fed mice demonstrated peri‐cellular hepatic fibrosis, inflammation, and steatosis typical of NASH. Liver fibrosis area was reduced by 40% in hAEC‐treated and hAEC‐CM‐treated mice. hAEC treatment significantly reduced pSMAD 2/3 signaling and the number of activated hepatic stellate cells and liver macrophages. Matrix metalloproteinase 2 and 9 gene and protein expression were variably affected. hAEC treatment did not alter the NASH activity score or metabolic parameters such as bodyweight, total cholesterol, or glucose tolerance. Conclusion Human amnion epithelial cell and hAEC‐CM significantly reduced hepatic inflammation and fibrosis in a diet‐induced non‐alcoholic fatty liver disease model. Although hAEC and hAEC‐CM did not affect the metabolic components of NASH, their therapeutic potential is promising and warrants further investigation.

show abstract

Section: Discussionmentioning

confidence: 99%

Human amnion epithelial cells and their soluble factors reduce liver fibrosis in murine non‐alcoholic steatohepatitis

Kuk

Hodge

Sun

et al. 2019

J of Gastro and Hepatol

Self Cite

View full text Add to dashboard Cite

show abstract

“…Briefly, SW480‐GFP‐Exos injected into a flow‐cell top plate by a syringe pump. Three videos (60 s per video) were recorded, merged, and analyzed by NTA software (Build 3.1.45) …”

Section: Methodsmentioning

confidence: 99%

Surfaceome of Exosomes Secreted from the Colorectal Cancer Cell Line SW480: Peripheral and Integral Membrane Proteins Analyzed by Proteolysis and TX114

Greening

Chen

et al. 2019

Proteomics

Self Cite

View full text Add to dashboard Cite

Exosomes are important bidirectional cell–cell communicators in normal and pathological physiology. Although exosomal surface membrane proteins (surfaceome) enable target cell recognition and are an attractive source of disease marker, they are poorly understood. Here, a comprehensive surfaceome analysis of exosomes secreted by the colorectal cancer cell line SW480 is described. Sodium carbonate extraction/Triton X‐114 phase separation and mild proteolysis (proteinase K, PK) of intact exosomes is used in combination with label‐free quantitative mass spectrometry to identify 1025 exosomal proteins of which 208 are predicted to be integral membrane proteins (IMPs) according to TOPCONS and GRAVY scores. Interrogation of UniProt database‐annotated proteins reveals 124 predicted peripherally‐associated membrane proteins (PMPs). Surprisingly, 108 RNA‐binding proteins (RBPs)/RNA nucleoproteins (RNPs) are found in the carbonate/Triton X‐114 insoluble fraction. Mild PK treatment of SW480‐GFP labeled exosomes reveal 58 proteolytically cleaved IMPs and 14 exoplasmic PMPs (e.g., CLU/GANAB/LGALS3BP). Interestingly, 18 RBPs/RNPs (e.g., EIF3L/RPL6) appear bound to the outer exosome surface since they are sensitive to PK proteolysis. The finding that outer surface‐localized miRNA Let‐7a‐5p is RNase A–resistant, but degraded by a combination of RNase A/PK treatment suggests exosomal miRNA species also reside on the outer surface of exosomes bound to RBPs/RNPs.

show abstract

“…Additionally, the injury‐induced production of pro‐inflammatory molecules such as tissue factor and monocyte chemoattractant protein‐1 by islets activates the innate immune response at the site of implantation, with subsequent loss of graft function . Human AECs counter pro‐inflammatory events in several models of inflammatory disease, by attenuating proliferation of specific immune cell populations and inflammatory cytokine production within damaged tissues, whilst also orchestrating the transition of T‐cells and monocytes from pro‐ to anti‐inflammatory regulatory profiles . Such functions would oppose the injurious impact of islet‐derived pro‐inflammatory molecules during RCCS co‐culture and after transplantation.…”

Section: Discussionmentioning

confidence: 99%

“…This offers the ability to alter the responsiveness of immune cell populations, especially those with direct involvement in islet graft rejection, whilst proffering trophic support . Amnion‐derived stem cells (ASC) exhibit immune‐privilege, most likely via low‐level expression of surface MHC classes I and II, whilst the factors within the ASC secretome include a range of pro‐angiogenic, cell trophic, anti‐inflammatory and immunomodulatory cytokines . Despite these potential benefits in the context of clinical islet allo‐transplantation, the behaviour of human ASC populations for xenogenic immune events has not been widely characterized.…”

Section: Introductionmentioning

confidence: 99%

Rotational culture and integration with amniotic stem cells reduce porcine islet immunoreactivity in vitro and slow xeno‐rejection in a murine model of islet transplantation

Zafar

Lee

Paget

et al. 2019

Xenotransplantation

View full text Add to dashboard Cite

Background Pre‐transplant modification of porcine islets may improve their suitability for clinical use in diabetes management by supporting graft function and reducing the potential for xeno‐rejection. The present study investigates intra‐graft incorporation of stem cells that secrete beta (β)‐cell trophic and immunomodulatory factors to preserve function and alter immune cell responsiveness to porcine islets. Methods Isolated porcine islets were maintained in a three‐dimensional rotational cell culture system (RCCS) to facilitate aggregation with human amniotic epithelial cells (AECs). Assembled islet constructs were assessed for functional integrity and ability to avoid xeno‐recognition by CD4+ T‐cells using mixed islet:lymphocyte reaction assays. To determine whether stem cell‐mediated modification of porcine islets provided a survival advantage over native islets, structural integrity was examined in a pig‐to‐mouse islet transplant model. Results Rotational cell culture system supported the formation of porcine islet:AEC aggregates with improved insulin‐secretory capacity compared to unmodified islets, whilst the xeno‐response of purified CD4+ T‐cells to AEC‐bearing grafts was significantly (P < 0.05) attenuated. Transplanted AEC‐bearing grafts demonstrated slower rejection in immune‐competent recipients compared to unmodified islets. Conclusions/interpretation Rotational culture enables pre‐transplant modification of porcine islets by integration with immunomodulatory stem cells capable of subduing xeno‐reactivity to CD4+ T‐cells. This reduces islet rejection and offers translational potential to widen availability and improve the clinical effectiveness of islet transplantation.

show abstract

The Human Amnion Epithelial Cell Secretome Decreases Hepatic Fibrosis in Mice with Chronic Liver Fibrosis

Cited by 71 publications

References 75 publications

Human amnion epithelial cells and their soluble factors reduce liver fibrosis in murine non‐alcoholic steatohepatitis

Human amnion epithelial cells and their soluble factors reduce liver fibrosis in murine non‐alcoholic steatohepatitis

Surfaceome of Exosomes Secreted from the Colorectal Cancer Cell Line SW480: Peripheral and Integral Membrane Proteins Analyzed by Proteolysis and TX114

Rotational culture and integration with amniotic stem cells reduce porcine islet immunoreactivity in vitro and slow xeno‐rejection in a murine model of islet transplantation

Contact Info

Product

Resources

About