Fibroblast spheroids as a model to study sustained fibroblast quiescence and their crosstalk with tumor cells

Salmenperä, Pertteli; Karhemo, Piia-Riitta; Räsänen, Kati; Laakkonen, Pirjo; Vaheri, Antti

doi:10.1016/j.yexcr.2016.05.005

Cited by 16 publications

(12 citation statements)

References 32 publications

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“…In fact, in these situations several proteases, destroying ECM structure, liberate fibroblasts from ECM and trigger fibroblasts clusters formation. 9 …”

Section: Discussionmentioning

confidence: 99%

Generation and analysis of spheroids from human primary skin myofibroblasts: an experimental system to study myofibroblasts deactivation

et al. 2017

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Myofibroblasts are activated fibroblasts involved in tissue repair and cancer. They are characterized by de novo expression of α-smooth muscle actin (α-SMA), immunoregulatory phenotype and paracrine interaction with normal and tumorigenic cells leading to cell proliferation. At the end of wound-healing myofibroblasts undergo apoptotic cell death, whereas in vitro-activated fibroblasts are also subjected to a programmed necrosis-like cell death, termed nemosis, associated with cyclooxygenase-2 (COX-2) expression induction and inflammatory response. Furthermore, myofibroblasts form clusters during wound healing, fibrotic states and tumorigenesis. In this study, we generated and analysed clusters such as spheroids from human primary cutaneous myofibroblasts, which represent a part of stromal microenvironment better than established cell lines. Therefore, we evaluated apoptotic or necrotic cell death, inflammation and activation markers during myofibroblasts clustering. The spheroids formation did not trigger apoptosis, necrotic cell death and COX-2 protein induction. The significant decrease of α-SMA in protein extracts of spheroids, the cytostatic effect exerted by spheroids conditioned medium on both normal and cancer cell lines and the absence of proliferation marker Ki-67 after 72 h of three-dimensional culture indicated that myofibroblasts have undergone a deactivation process within spheroids. The cells of spheroids reverted to adhesion growth preserved their proliferation capability and can re-acquire a myofibroblastic phenotype. Moreover, the spontaneous formation of clusters on plastic and glass substrates suggests that aggregates formation could be a physiological feature of cutaneous myofibroblasts. This study represents an experimental model to analyse myofibroblasts deactivation and suggests that fibroblast clusters could be a cell reservoir regulating tissues turnover.

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“…In fact, in these situations several proteases, destroying ECM structure, liberate fibroblasts from ECM and trigger fibroblasts clusters formation. 9 …”

Section: Discussionmentioning

confidence: 99%

Generation and analysis of spheroids from human primary skin myofibroblasts: an experimental system to study myofibroblasts deactivation

et al. 2017

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“…Further, quiescent muscle stem cells are known to secrete CIAPIN 1 to maintain the satellite cells (Chan et al, ). While most of the above described studies, on role of cytokines/chemokines, were done in quiescent stem cells, a recent report showed that quiescent fibroblasts also show an inflammatory secretory phenotype similar to senescence (Salmenperä, Karhemo, Räsänen, Laakkonen, & Vaheri, ). Our study now emphasizes a role of quiescence‐associated secretory phenotype (QASP) as an important characteristic feature of even transient growth arrest.…”

Section: Discussionmentioning

confidence: 99%

Differentially regulated gene expression in quiescence versus senescence and identification of ARID5A as a quiescence associated marker

Anwar

Sen

Aggarwal

et al. 2017

Journal Cellular Physiology

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In multicellular organisms majority of the cells remain in a non-dividing states of either quiescence (reversible) or senescence (irreversible). In the present study, gene expression signatures unique to quiescence and senescence were identified using microarray in osteosarcoma cell line, U2OS. It was noted that certain genes and pathways like NOD pathway was shared by both the growth arrest conditions. A major highlight of the present study was increased expression of number of chemokines and cytokines in both quiescence and senescence. While senescence-associated secretory phenotype (SASP) is well known, the quiescence-associated secretory phenotype (QASP) is relatively unknown and appeared novel in this study. ARID5A, a subunit of SWI/SNF complex was identified as a quiescence associated gene. The endogenous expression of ARID5A increased during serum starved condition of quiescence. Overexpression of ARID5A resulted in more number of cells in G0/G1 phase of cell cycle. Further ARID5A overexpressing cells when subjected to serum starvation showed a pronounced secretory phenotype. Overall, the present work has identified gene expression signatures which can distinguish quiescence from senescence.

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“…Human colon Matrigel -rich in growth factors, signal factors for cell proliferation -expensive and animal derived PC-3M, PrCa, NCI-H600 [74], HepG2 [75], A235, B16F10 [76] agar -damage on cells by forces from gel formation inside the agar -excellent mechanical properties human foreskin dermal fibroblasts [77], cortical cell [78] alginate -rapid formation of hydrogel scaffolds -strong chemicals required to break hydrogel networks to harvest MCSs human fat-derived stromal vascular fraction cells [79], human colon cancer cells (HCT116) [80] fibrin -promoting cell attachment -high cell viability human mesenchymal stem cell [81], B16-F1…”

Section: Micro-mouldingmentioning

confidence: 99%

Advances in multicellular spheroids formation

Cui¹,

Hartanto²,

Zhang³

2017

J. R. Soc. Interface.

409

336

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Three-dimensional multicellular spheroids (MCSs) have a complex architectural structure, dynamic cell -cell/cell -matrix interactions and bio-mimicking in vivo microenvironment. As a fundamental building block for tissue reconstruction, MCSs have emerged as a powerful tool to narrow down the gap between the in vitro and in vivo model. In this review paper, we discussed the structure and biology of MCSs and detailed fabricating methods. Among these methods, the approach in microfluidics with hydrogel support for MCS formation is promising because it allows essential cell -cell/cell -matrix interactions in a confined space.

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Fibroblast spheroids as a model to study sustained fibroblast quiescence and their crosstalk with tumor cells

Cited by 16 publications

References 32 publications

Generation and analysis of spheroids from human primary skin myofibroblasts: an experimental system to study myofibroblasts deactivation

Generation and analysis of spheroids from human primary skin myofibroblasts: an experimental system to study myofibroblasts deactivation

Differentially regulated gene expression in quiescence versus senescence and identification of ARID5A as a quiescence associated marker

Advances in multicellular spheroids formation

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