Infrapatellar Fat Pad Stem Cells Responsiveness to Microenvironment in Osteoarthritis: From Morphology to Function

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Abstract

Recently, infrapatellar fat pad (IFP) has been considered as a source of stem cells for cartilage regeneration in osteoarthritis (OA) due to their ability for differentiation into chondrocytes. However, stressful conditions, like that related to OA, may induce a pathogenic reprograming. The aim of this study was to characterize the structural and functional properties of a new population of stem cells isolated from osteoarthritic infrapatellar fat pad (OA-IFP). Nine OA patients undergoing total knee arthroplasty (TKA) were enrolled in this study [median age = 74 years, interquartile range (IQR) = 78.25-67.7; median body mass index = 29.4 Kg/m ², IQR = 31.7-27.4]. OA-IFP stem cells were isolated and characterized for morphology, stemness, metabolic profile and multi-differentiative potential by transmission electron microscopy, flow cytometric analysis, gene expression study and cytochemistry. OA-IFP stem cells displayed a spindle-like morphology, self-renewal potential and responsiveness (CD44, CD105, VEGFR2, FGFR2, IL1R, and IL6R) to microenvironmental stimuli. Characterized by high grade of stemness ( STAT3, NOTCH1, c-Myc, OCT-4, KLF4, and NANOG), the cells showed peculiar immunophenotypic properties (CD73 ⁺/CD39 ⁺/CD90 ⁺/CD105 ⁺/CD44 ^–/+/CD45 ^–). The expression of HLA-DR, CD34, Fas and FasL was indicative of a possible phenotypic reprograming induced by inflammation. Moreover, the response to mechanical stimuli together with high expression level of COL1A1 gene, suggested their possible protective response against in vivo mechanical overloading. Conversely, the low expression of CD38/NADase was indicative of their inability to counteract NAD ⁺-mediated OA inflammation. Based on the ultrastructural, immunophenotypic and functional characterization, OA-IFP stem cells were hypothesized to be primed by the pathological environment and to exert incomplete protective activity from OA inflammation.

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Most cited references 57

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Oligosaccharides of Hyaluronan Activate Dendritic Cells via Toll-like Receptor 4

Christian Termeer, Frauke Benedix, Jonathon Sleeman … (2002)

Low molecular weight fragmentation products of the polysaccharide of Hyaluronic acid (sHA) produced during inflammation have been shown to be potent activators of immunocompetent cells such as dendritic cells (DCs) and macrophages. Here we report that sHA induces maturation of DCs via the Toll-like receptor (TLR)-4, a receptor complex associated with innate immunity and host defense against bacterial infection. Bone marrow–derived DCs from C3H/HeJ and C57BL/10ScCr mice carrying mutant TLR-4 alleles were nonresponsive to sHA-induced phenotypic and functional maturation. Conversely, DCs from TLR-2–deficient mice were still susceptible to sHA. In accordance, addition of an anti–TLR-4 mAb to human monocyte–derived DCs blocked sHA-induced tumor necrosis factor α production. Western blot analysis revealed that sHA treatment resulted in distinct phosphorylation of p38/p42/44 MAP-kinases and nuclear translocation of nuclear factor (NF)-κB, all components of the TLR-4 signaling pathway. Blockade of this pathway by specific inhibitors completely abrogated the sHA-induced DC maturation. Finally, intravenous injection of sHA-induced DC emigration from the skin and their phenotypic and functional maturation in the spleen, again depending on the expression of TLR-4. In conclusion, this is the first report that polysaccharide degradation products of the extracellular matrix produced during inflammation might serve as an endogenous ligand for the TLR-4 complex on DCs.

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The extra domain A of fibronectin activates Toll-like receptor 4.

Y Okamura, M Watari, E S Jerud … (2001)

Cellular fibronectin, which contains an alternatively spliced exon encoding type III repeat extra domain A (EDA), is produced in response to tissue injury. Fragments of fibronectin have been implicated in physiological and pathological processes, especially tissue remodeling associated with inflammation. Because EDA-containing fibronectin fragments produce cellular responses similar to those provoked by bacterial lipopolysaccharide (LPS), we examined the ability of recombinant EDA to activate Toll-like receptor 4 (TLR4), the signaling receptor stimulated by LPS. We found that recombinant EDA, but not other recombinant fibronectin domains, activates human TLR4 expressed in a cell type (HEK 293 cells) that normally lacks this Toll-like receptor. EDA stimulation of TLR4 was dependent upon co-expression of MD-2, a TLR4 accessory protein. Unlike LPS, the activity of EDA was heat-sensitive and persisted in the presence of the LPS-binding antibiotic polymyxin B and a potent LPS antagonist, E5564, which completely suppressed LPS activation of TLR4. These observations provided a mechanism by which EDA-containing fibronectin fragments promote expression of genes involved in the inflammatory response.

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Increased ER-mitochondrial coupling promotes mitochondrial respiration and bioenergetics during early phases of ER stress.

Roberto Bravo, José Vicencio, Valentina Parra … (2011)

Increasing evidence indicates that endoplasmic reticulum (ER) stress activates the adaptive unfolded protein response (UPR), but that beyond a certain degree of ER damage, this response triggers apoptotic pathways. The general mechanisms of the UPR and its apoptotic pathways are well characterized. However, the metabolic events that occur during the adaptive phase of ER stress, before the cell death response, remain unknown. Here, we show that, during the onset of ER stress, the reticular and mitochondrial networks are redistributed towards the perinuclear area and their points of connection are increased in a microtubule-dependent fashion. A localized increase in mitochondrial transmembrane potential is observed only in redistributed mitochondria, whereas mitochondria that remain in other subcellular zones display no significant changes. Spatial re-organization of these organelles correlates with an increase in ATP levels, oxygen consumption, reductive power and increased mitochondrial Ca²⁺ uptake. Accordingly, uncoupling of the organelles or blocking Ca²⁺ transfer impaired the metabolic response, rendering cells more vulnerable to ER stress. Overall, these data indicate that ER stress induces an early increase in mitochondrial metabolism that depends crucially upon organelle coupling and Ca²⁺ transfer, which, by enhancing cellular bioenergetics, establishes the metabolic basis for the adaptation to this response.

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Author and article information

Contributors

Elena Stocco: URI : http://loop.frontiersin.org/people/567631/overview

Silvia Barbon: URI : http://loop.frontiersin.org/people/800120/overview

Monica Piccione: URI : http://loop.frontiersin.org/people/820439/overview

Elisa Belluzzi: URI : http://loop.frontiersin.org/people/304657/overview

Assunta Pozzuoli: URI : http://loop.frontiersin.org/people/784147/overview

Marco Rossato: URI : http://loop.frontiersin.org/people/627742/overview

Andrea Porzionato: URI : http://loop.frontiersin.org/people/181414/overview

Rosa Di Liddo: URI : http://loop.frontiersin.org/people/784258/overview

Raffaele De Caro: URI : http://loop.frontiersin.org/people/784086/overview

Veronica Macchi: URI : http://loop.frontiersin.org/people/191374/overview

Journal

Journal ID (nlm-ta): Front Cell Dev Biol

Journal ID (iso-abbrev): Front Cell Dev Biol

Journal ID (publisher-id): Front. Cell Dev. Biol.

Title: Frontiers in Cell and Developmental Biology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 2296-634X

Publication date (Electronic): 10 December 2019

Publication date Collection: 2019

Volume: 7

Electronic Location Identifier: 323

Affiliations

[1] ¹Department of Neurosciences, Institute of Human Anatomy, University of Padova , Padua, Italy

[2] ²LifeLab Program, Consorzio per la Ricerca Sanitaria (CORIS) , Padua, Italy

[3] ³Foundation for Biology and Regenerative Medicine, Tissue Engineering and Signaling ONLUS , Padua, Italy

[4] ⁴Department of Pharmaceutical and Pharmacological Sciences, University of Padova , Padua, Italy

[5] ⁵Musculoskeletal Pathology and Oncology Laboratory, Department of Surgery, Oncology and Gastroenterology DiSCOG, University of Padova , Padua, Italy

[6] ⁶Department of Orthopaedics and Orthopaedic Oncology, University of Padova , Padua, Italy

[7] ⁷Rheumatology Unit, Department of Medicine – DIMED, University Hospital of Padova , Padua, Italy

[8] ⁸Clinica Medica 3, Department of Medicine – DIMED, University of Padova , Padua, Italy

Author notes

Edited by: Gianluca Carnevale, University of Modena and Reggio Emilia, Italy

Reviewed by: Laura Bertoni, University of Modena and Reggio Emilia, Italy; Stefania Croci, Local Health Authority of Reggio Emilia (IRCCS), Italy; Burhan Gharaibeh, University of Pittsburgh, United States

*Correspondence: Rosa Di Liddo, rosa.diliddo@ 123456unipd.it

Raffaele De Caro, raffaele.decaro@ 123456unipd.it

^†These authors have contributed equally to this work

This article was submitted to Stem Cell Research, a section of the journal Frontiers in Cell and Developmental Biology

Article

DOI: 10.3389/fcell.2019.00323

PMC ID: 6914674

PubMed ID: 31921840

SO-VID: 972f54af-70fc-47bb-a496-e84dd4f9d756

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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 01 August 2019

Date accepted : 25 November 2019

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Figures: 5, Tables: 3, Equations: 1, References: 66, Pages: 13, Words: 0

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Infrapatellar Fat Pad Stem Cells Responsiveness to Microenvironment in Osteoarthritis: From Morphology to Function

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Most cited references 57

Oligosaccharides of Hyaluronan Activate Dendritic Cells via Toll-like Receptor 4

The extra domain A of fibronectin activates Toll-like receptor 4.

Increased ER-mitochondrial coupling promotes mitochondrial respiration and bioenergetics during early phases of ER stress.

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