Our Three-Year Planning (2025-2027) for Research

MSCs are used in the biomedical field for their immunomodulatory and regenerative properties, attributable to the release of a secretome rich in paracrine factors, including cytokines, growth factors and EVs. The use of the MSC secretome represents a cell-free therapeutic approach, potentially able to overcome the limitations of cell therapies, such as immunogenicity, difficulty in engraftment and regulatory complexities.

Placental MSCs, derived from the amniotic membrane and the Wharton's jelly, offer an advantage in terms of abundance and absence of ethical issues, while bone marrow MSCs, extensively characterized, constitute a reference model for the evaluation of the efficacy and safety of the secretome.

Degenerative diseases often have an immune-mediated basis and include neurodegenerative diseases, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). These conditions share common pathogenic mechanisms, including chronic neuroinflammation, oxidative stress and dysregulation of tissue homeostasis. The lack of curative treatments makes it necessary to develop strategies capable of modulating the pathological microenvironment through synergistic mechanisms.

The integration of the MSC secretome with advanced nanodelivery and tissue engineering systems represents an innovative therapeutic approach, improving bioavailability, stability and targeting, with a high potential for clinical translation.

Chronic inflammation and immune dysregulation are central elements in the pathogenesis of many immune-mediated degenerative diseases. The MSC secretome exerts a pleiotropic action, modulating inflammation, promoting neuroprotection and promoting tissue regeneration through distinct and complementary mechanisms:

• Selective immunomodulation by inhibiting pro-inflammatory microglial activation (M1 phenotype) and promoting the anti-inflammatory phenotype (M2); increasing the population of regulatory T cells (Treg) and reducing the Th1/Th17 response (10.1111/jcmm.14113, 10.1016/j.neurobiolaging.2013.03.029, 10.1002/art.38206).

• Neuroprotection through the promotion of neuronal survival and synaptic plasticity via the release of neurotrophic factors, including BDNF and GDNF (10.1016/j.scr.2009.02.006, 10.1186/s11658-022-00359-z).

·       Modulation of inflammation, with reduction of the production of pro-inflammatory cytokines (e.g. TNF-α, IL-6) and increase of anti-inflammatory mediators (e.g. IL-10, TGF-β) (10.1016/j.neurobiolaging.2013.03.029, 10.3727/096368913X672181, 10.1111/nan.12319), promoting the restoration of tissue homeostasis.

• Regulation of the pathological microenvironment, through EVs, which transport microRNAs and bioactive proteins with targeted action on inflammatory and neurodegenerative processes.

The characterization of the therapeutic profile of the secretome will allow the optimization of its clinical application, adapting it to the target pathology and specific physiopathological mechanisms. Directly usable or delivered via nanodelivery and tissue engineering, the secretome and its fractions (EVs, EV-depleted fraction) will be able to benefit from advanced controlled release and localized administration systems, improving their stability, bioavailability and therefore maximizing their therapeutic potential and clinical translation.

A. Analysis of the immunomodulatory and neuroprotective properties of the secretome: study of the mechanisms of action responsible for tissue regeneration; identification of the biomarkers related to the therapeutically most effective fraction.

B. Development of a GMP-compliant production process: optimization of isolation, purification and conservation processes; validation of the safety profile and compliance with AIFA and EMA regulatory standards; development of advanced delivery and tissue engineering strategies

C. Preclinical evaluation and clinical translation: Analysis of efficacy and safety on preclinical models in vitro and in vivo; definition of quality criteria for the transition to phase I/II clinical studies.

The development of a MSC secretome-based therapy offers an advanced option for diseases without curative treatments, ensuring safety, reproducibility and scalability compared to cell therapies, thanks to a multidisciplinary approach and integration with advanced delivery systems to improve stability and efficacy. Expected results include:

• Definition of the mechanism of action of MSCs, of the secretome and of the various fractions including EVs.

• Identification of the fraction of the MSC secretome having the maximum therapeutic effect, validated on preclinical models for specific immune-mediated diseases, including neurodegenerative diseases.

• Development of a GMP-compliant protocol, ensuring reproducibility, quality and stability of the product.

• Preclinical validation of the safety and efficacy of the secretome and its fractions with nanoparticles and functionalized scaffolds.

• Development of advanced nanodelivery and tissue engineering systems.