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ILENIA MASTROLIA

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Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto sede via Campi

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Pubblicazioni

2022 - Autologous Marrow Mesenchymal Stem Cell Driving Bone Regeneration in a Rabbit Model of Femoral Head Osteonecrosis [Articolo su rivista]
Mastrolia, I.; Giorgini, A.; Murgia, A.; Loschi, P.; Petrachi, T.; Rasini, V.; Pinelli, M.; Pinto, V.; Lolli, F.; Chiavelli, C.; Grisendi, G.; Baschieri, M. C.; Santis, G. D.; Catani, F.; Dominici, M.; Veronesi, E.
abstract

Osteonecrosis of the femoral head (ONFH) is a progressive degenerative disease that ultimately requires a total hip replacement. Mesenchymal stromal/stem cells (MSCs), particularly the ones isolated from bone marrow (BM), could be promising tools to restore bone tissue in ONFH. Here, we established a rabbit model to mimic the pathogenic features of human ONFH and to challenge an autologous MSC-based treatment. ON has been originally induced by the synergic combination of surgery and steroid administration. Autologous BM-MSCs were then implanted in the FH, aiming to restore the damaged tissue. Histological analyses confirmed bone formation in the BM-MSC treated rabbit femurs but not in the controls. In addition, the model also allowed investigations on BM-MSCs isolated before (ON-BM-MSCs) and after (ON+BM-MSCs) ON induction to dissect the impact of ON damage on MSC behavior in an affected microenvironment, accounting for those clinical approaches foreseeing MSCs generally isolated from affected patients. BM-MSCs, isolated before and after ON induction, revealed similar growth rates, immunophenotypic profiles, and differentiation abilities regardless of the ON. Our data support the use of ON+BM-MSCs as a promising autologous therapeutic tool to treat ON, paving the way for a more consolidated use into the clinical settings.

2022 - Human Adipose Mesenchymal Stromal/Stem Cells Improve Fat Transplantation Performance [Articolo su rivista]
Piccinno, M. S.; Petrachi, T.; Pignatti, M.; Murgia, A.; Grisendi, G.; Candini, O.; Resca, E.; Bergamini, V.; Ganzerli, F.; Portone, A.; Mastrolia, I.; Chiavelli, C.; Castelli, I.; Bernabei, D.; Tagliazucchi, M.; Bonetti, E.; Lolli, F.; De Santis, G.; Dominici, M.; Veronesi, E.
abstract

The resorption rate of autologous fat transfer (AFT) is 40–60% of the implanted tissue, requiring new surgical strategies for tissue reconstruction. We previously demonstrated in a rabbit model that AFT may be empowered by adipose-derived mesenchymal stromal/stem cells (AD-MSCs), which improve graft persistence by exerting proangiogenic/anti-inflammatory effects. However, their fate after implantation requires more investigation. We report a xenograft model of adipose tissue engineering in which NOD/SCID mice underwent AFT with/without human autologous AD-MSCs and were monitored for 180 days (d). The effect of AD-MSCs on AFT grafting was also monitored by evaluating the expression of CD31 and F4/80 markers. Green fluorescent protein-positive AD-MSCs (AD-MSC-GFP) were detected in fibroblastoid cells 7 days after transplantation and in mature adipocytes at 60 days, indicating both persistence and differentiation of the implanted cells. This evidence also correlated with the persistence of a higher graft weight in AFT-AD-MSC compared to AFT alone treated mice. An observation up to 180 d revealed a lower resorption rate and reduced lipidic cyst formation in the AFT-AD-MSC group, suggesting a long-term action of AD-MSCs in support of AFT performance and an anti-inflammatory/proangiogenic activity. Together, these data indicate the protective role of adipose progenitors in autologous AFT tissue resorption.

2021 - Mesenchymal stem cell immunomodulation: In pursuit of controlling COVID-19 related cytokine storm [Articolo su rivista]
Song, N.; Wakimoto, H.; Rossignoli, F.; Bhere, D.; Ciccocioppo, R.; Chen, K. -S.; Khalsa, J. K.; Mastrolia, I.; Samarelli, A. V.; Dominici, M.; Shah, K.
abstract

The Coronavirus disease 2019 (COVID-19) pandemic has grown to be a global public health crisis with no safe and effective treatments available yet. Recent findings suggest that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the coronavirus pathogen that causes COVID-19, could elicit a cytokine storm that drives edema, dysfunction of the airway exchange, and acute respiratory distress syndrome in the lung, followed by acute cardiac injury and thromboembolic events leading to multiorgan failure and death. Mesenchymal stem cells (MSCs), owing to their powerful immunomodulatory abilities, have the potential to attenuate the cytokine storm and have therefore been proposed as a potential therapeutic approach for which several clinical trials are underway. Given that intravenous infusion of MSCs results in a significant trapping in the lung, MSC therapy could directly mitigate inflammation, protect alveolar epithelial cells, and reverse lung dysfunction by normalizing the pulmonary microenvironment and preventing pulmonary fibrosis. In this review, we present an overview and perspectives of the SARS-CoV-2 induced inflammatory dysfunction and the potential of MSC immunomodulation for the prevention and treatment of COVID-19 related pulmonary disease.

2021 - The Role of Exosomes in Breast Cancer Diagnosis. [Articolo su rivista]
Piombino, C; Mastrolia, I; Omarini, C; Candini, O; Dominici, M; Piacentini, F; Toss, A.
abstract

The importance of molecular re-characterization of metastatic disease with the purpose of monitoring tumor evolution has been acknowledged in numerous clinical guidelines for the management of advanced malignancies. In this context, an attractive alternative to overcome the limitations of repeated tissue sampling is represented by the analysis of peripheral blood samples as a 'liquid biopsy'. In recent years, liquid biopsies have been studied for the early diagnosis of cancer, the monitoring of tumor burden, tumor heterogeneity and the emergence of molecular resistance, along with the detection of minimal residual disease. Interestingly, liquid biopsy consents the analysis of circulating tumor cells, circulating tumor DNA and extracellular vesicles (EVs). In particular, EVs play a crucial role in cell communication, carrying transmembrane and nonmembrane proteins, as well as metabolites, lipids and nucleic acids. Of all EVs, exosomes mirror the biological fingerprints of the parental cells from which they originate, and therefore, are considered one of the most promising predictors of early cancer diagnosis and treatment response. The present review discusses current knowledge on the possible applications of exosomes in breast cancer (BC) diagnosis, with a focus on patients at higher risk.

2020 - Arming Mesenchymal Stromal/Stem Cells Against Cancer: Has the Time Come? [Articolo su rivista]
Golinelli, Giulia; Mastrolia, Ilenia; Aramini, Beatrice; Masciale, Valentina; Pinelli, Massimo; Pacchioni, Lucrezia; Casari, Giulia; Dall’Ora, Massimiliano; Botelho Pereira Soares, Milena; Kauanna Fonseca Damasceno, Patrícia; Nascimento Silva, Daniela; Dominici, Massimo; Grisendi, Giulia
abstract

Since mesenchymal stromal/stem cells (MSCs) were discovered, researchers have been drawn to study their peculiar biological features, including their immune privileged status and their capacity to selectively migrate into inflammatory areas, including tumors. These properties make MSCs promising cellular vehicles for the delivery of therapeutic molecules in the clinical setting. In recent decades, the engineering of MSCs into biological vehicles carrying anticancer compounds has been achieved in different ways, including the loadingof MSCs with chemotherapeutics or drug functionalized nanoparticles (NPs), genetic modifications to force the production of anticancer proteins, and the use of oncolytic viruses. Recently, it has been demonstrated that wild-type and engineered MSCs can release extracellular vesicles (EVs) that contain therapeutic agents. Despite the enthusiasm for MSCs as cyto-pharmaceutical agents, many challenges, including controlling the fate of MSCs after administration, must still be considered. Preclinical results demonstrated that MSCs accumulate in lung, liver, and spleen, which could prevent their engraftment into tumor sites. For this reason, physical, physiological, and biological methods have been implemented to increase MSC concentration in the target tumors. Currently, there are more than 900 registered clinical trials using MSCs. Only a small fraction of these are investigating MSC-based therapies for cancer, but the number of these clinical trials is expected to increase as technology and our understanding of MSCs improve. This review will summarize MSC-based antitumor therapies to generate an increasing awareness of their potential and limits to accelerate their clinical translation.

2019 - Challenges in Clinical Development of Mesenchymal Stromal/Stem Cells: Concise Review [Articolo su rivista]
Mastrolia, I.; Foppiani, E. M.; Murgia, A.; Candini, O.; Samarelli, A. V.; Grisendi, G.; Veronesi, E.; Horwitz, E. M.; Dominici, M.
abstract

Identified 50 years ago, mesenchymal stromal/stem cells (MSCs) immediately generated a substantial interest among the scientific community because of their differentiation plasticity and hematopoietic supportive function. Early investigations provided evidence of a relatively low engraftment rate and a transient benefit for challenging congenital and acquired diseases. The reasons for these poor therapeutic benefits forced the entire field to reconsider MSC mechanisms of action together with their ex vivo manipulation procedures. This phase resulted in advances in MSCs processing and the hypothesis that MSC-tissue supportive functions may be prevailing their differentiation plasticity, broadening the spectrum of MSCs therapeutic potential far beyond their lineage-restricted commitments. Consequently, an increasing number of studies have been conducted for a variety of clinical indications, revealing additional challenges and suggesting that MSCs are still lagging behind for a solid clinical translation. For this reason, our aim was to dissect the current challenges in the development of still promising cell types that, after more than half a century, still need to reach their maturity. Stem Cells Translational Medicine 2019;8:1135–1148.

2019 - Human mesenchymal stem cell combined with a new strontium-enriched bioactive glass: An ex-vivo model for Bone Regeneration [Articolo su rivista]
Bellucci, D.; Veronesi, E.; Strusi, V.; Petrachi, T.; Murgia, A.; Mastrolia, I.; Dominici, M.; Cannillo, V.
abstract

A 3D cellular model that mimics the potential clinical application of a biomaterial is here applied for the first time to a bioactive glass, in order to assess its biological potential. A recently developed bioactive glass (BGMS10), whose composition contained strontium and magnesium, was produced in the form of granules and fully investigated in terms of biocompatibility in vitro. Apart from standard biological characterization (Simulated Body Fluid (SBF) testing and biocompatibility as per ISO10993), human bone marrow mesenchymal stromal/stem cells (BM-MSCs) were used to investigate the performance of the bioactive glass granules in an innovative 3D cellular model. The results showed that BGMS10 supported human BM-MSCs adhesion, colonization, and bone differentiation. Thus, bioactive glass granules seem to drive osteogenic differentiation and thus look particularly promising for orthopedic applications, bone tissue engineering and regenerative medicine.

2019 - Impact of HOXB7 overexpression on human adipose-derived mesenchymal progenitors [Articolo su rivista]
Foppiani, E. M.; Candini, O.; Mastrolia, I.; Murgia, A.; Grisendi, G.; Samarelli, A. V.; Boscaini, G.; Pacchioni, L.; Pinelli, M.; De Santis, G.; Horwitz, E. M.; Veronesi, E.; Dominici, M.
abstract

Background: The ex vivo expansion potential of mesenchymal stromal/stem cells (MSC) together with their differentiation and secretion properties makes these cells an attractive tool for transplantation and tissue engineering. Although the use of MSC is currently being tested in a growing number of clinical trials, it is still desirable to identify molecular markers that may help improve their performance both in vitro and after transplantation. Methods: Recently, HOXB7 was identified as a master player driving the proliferation and differentiation of bone marrow mesenchymal progenitors. In this study, we investigated the effect of HOXB7 overexpression on the ex vivo features of adipose mesenchymal progenitors (AD-MSC). Results: HOXB7 increased AD-MSC proliferation potential, reduced senescence, and improved chondrogenesis together with a significant increase of basic fibroblast growth factor (bFGF) secretion. Conclusion: While further investigations and in vivo models shall be applied for better understanding, these data suggest that modulation of HOXB7 may be a strategy for innovative tissue regeneration applications.

2019 - MSC-delivered soluble TRAIl and paclitaxel as novel combinatory treatment for pancreatic adenocarcinoma [Articolo su rivista]
Rossignoli, Filippo; Spano, Carlotta; Grisendi, Giulia; Foppiani, Elisabetta Manuela; Golinelli, Giulia; Mastrolia, Ilenia; Bestagno, Marco; Candini, Olivia; Petrachi, Tiziana; Recchia, Alessandra; Miselli, Francesca; Rovesti, Giulia; Orsi, Giulia; Veronesi, Elena; Medici, Gregorio; Petocchi, Benedetta; Pinelli, Massimo; Horwitz, Edwin M.; Conte, Pierfranco; Dominici, Massimo
abstract

Pancreatic cancer is the fourth leading cause of cancer death in western countries with more than 100,000 new cases per year in Europe and a mortality rate higher than 90%. In this scenario, advanced therapies based on gene therapies are emerging, thanks to a better understanding of tumour architecture and cancer cell alterations. We have demonstrated the efficacy of an innovative approach for pancreatic cancer based on mesenchymal stromal cells (MSC) genetically engineered to produce TNF-related Apoptosis Inducing Ligand (TRAIL). Here we investigated the combination of this MSC-based approach with the administration of a paclitaxel (PTX)-based chemotherapy to improve the potential of the treatment, also accounting for a possible resistance onset. Methods: Starting from the BXPC3 cell line, we generated and profiled a TRAIL-resistant model of pancreatic cancer, testing the impact of the combined treatment in vitro with specific cytotoxicity and metabolic assays. We then challenged the rationale in a subcutaneous mouse model of pancreatic cancer, assessing its effect on tumour size accounting stromal and parenchymal organization. Results: PTX was able to restore pancreatic cancer sensitivity to MSC-delivered TRAIL by reverting its pro-survival gene expression profile. The two compounds cooperate both in vitro and in vivo and the combined treatment resulted in an improved cytotoxicity on tumour cells. Conclusion: In summary, this study uncovers the potential of a combinatory approach between MSC-delivered TRAIL and PTX, supporting the combination of cell-based products and conventional chemotherapeutics as a tool to improve the efficacy of the treatments, also addressing possible mechanisms of resistance.

2017 - GD2 expression in breast cancer. [Articolo su rivista]
Orsi, Giulia; Barbolini, Monica; Ficarra, G; Tazzioli, Giovanni; Manni, Paola; Petrachi, Tiziana; Mastrolia, Ilenia; Orvieto, E; Spano, Maria Carlotta; Prapa, Malvina; Kaleci, Shaniko; D'Amico, Roberto; Guarneri, V; Dieci, Mv; Cascinu, Stefano; Conte, P; Piacentini, Federico; Dominici, Massimo
abstract

Breast cancer (BC) is a heterogeneous disease, including different subtypes having diverse incidence, drug-sensitivity and survival rates. In particular, claudin-low and basal-like BC have mesenchymal features with a dismal prognosis. Disialoganglioside GD2 is a typical neuroectodermal antigen expressed in a variety of cancers. Despite its potential relevance in cancer diagnostics and therapeutics, the presence and role of GD2 require further investigation, especially in BC. Therefore, we evaluated GD2 expression in a cohort of BC patients and its correlation with clinical-pathological features.Sixty-three patients with BC who underwent surgery without prior chemo- and/or radiotherapy between 2001 and 2014 were considered. Cancer specimens were analyzed by immunohistochemistry and GD2-staining was expressed according to the percentage of positive cells and by a semi-quantitative scoring system.Patient characteristics were heterogeneous by age at diagnosis, histotype, grading, tumor size, Ki-67 and receptor-status. GD2 staining revealed positive cancer cells in 59% of patients. Among them, 26 cases (41%) were labeled with score 1+ and 11 (18%) with score 2+. Notably, the majority of metaplastic carcinoma specimens stained positive for GD2. The univariate regression logistic analysis revealed a significant association of GD2 with triple-receptor negative phenotype and older age (> 78) at diagnosis.We demonstrate for the first time that GD2 is highly prevalent in a cohort of BC patients clustering on very aggressive BC subtypes, such as triple-negative and metaplastic variants.

2015 - cGMP-compliant transportation conditions for a prompt therapeutic use of marrow mesenchymal stromal/stem cells [Capitolo/Saggio]
Veronesi, Elena; Burns, Jorge Phillip Joaquin Sans; Murgia, Alba; Candini, Olivia; Rasini, Valeria; Mastrolia, Ilenia; Catani, Fabio; Paolucci, Paolo; Dominici, Massimo
abstract

We recently described conditions for safe 18-h manufacturer-to-patient transportation of freshly harvested hBM-MSC expanded under cGMP protocols using human platelet lysate (hPL), that allowed prompt use as an advanced therapeutic medicinal product. Here we outline important considerations when comparing different transportation conditions, highlighting that although cell transportation may involve a reduction in viability, this did not undermine the ultimate bone-forming regenerative potential of the cGMP-hBM-MSC population.