Metabolic-engineered stem cell-derived exosomes regulate rheumatoid arthritis macrophage heterogeneity

Although the class of rheumatoid arthritis (RA) treatment has made remarkable progress, but the lack of effective treatment is still a lot of patients
.
Recently, macrophage reprogramming the immune phenotype regulation has become the treatment of type rheumatoid arthritis one promising treatment strategies
.
Recently, researchers from the School of Engineering of Sungkyunkwan University published an article titled "Metabolically engineered stem cell-derived exosomes to regulate macrophage heterogeneity in rheumatoid arthritis" in Sci Adv
.
Here, the authors report that metabolically engineered exosomes have been surface-modified for targeted reprogramming of macrophages
.
Through tangential flow filtration, it can be easily derived from metabolic engineeringObtain qualified exosomes with high yield from


stem cells while maintaining their inherent immunomodulatory components .
When these exosomes were systematically injected into collagen-induced arthritis mice, these exosomes effectively accumulated in the inflamed joints and induced a series of anti-inflammatory events through macrophage phenotype regulation .
The level of therapeutic effect obtained with naked exosomes can be achieved with engineered exosomes with a dose 10 times less .
Based on the enhanced properties of the synovial microenvironment reprogramming, engineering exosomes showed a considerable potential for the treatment of type was developed arthritis in the next generation of drugs
.

Image source: https://pubmed.
ncbi.
nlm.
nih.
gov/34078596/

Rheumatoid arthritis (RA) is a debilitating and economically burdensome disease, affecting up to 2.
5% of the population in every country
.
In 2017, the global RA treatment market was valued at USD 23.
82 billion and is expected to reach USD 33.
96 billion by 2025
.
The pathogenesis of rheumatoid arthritis involves the infiltration of inflammatory cells, leading to cartilage destruction and bone erosion
.
Among the cells related to RA, M1 macrophages are considered to be the most important cells that lead to the formation and aggravation of lesions.
It releases various types of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6) and Interleukin-1 (IL-1)
.
Related traditional treatment methods focus on inhibiting the inflammatory process, for example, by inhibiting these cytokines or depleting m1 macrophages
.
At the same time, in view of the previously unknown insights into the plasticity and polarization of macrophages, restoration of the impaired lysis process in chronic inflammation by directly reversing the dominant phenotype from M1 to M2 has recently received great attention
.
New methods of cultivating a restorative environment have been conceived as closer to therapeutic interventions to cure rheumatoid arthritis by ending the pathological process
.
MesenchymeStem cells (mesenchymal stem cells, MSCs) have shown therapeutic potential by regulating the macrophage phenotype of rheumatoid arthritis (RA), but their allogeneic transplantation has poor survival rate and immunogenicity and is limited
.
Exosomes (exosome, exos) is secreted by virtually all cell types to extracellular vesicles intercellular communication (a diameter of 40 to 160 nm), has recently become a non-therapeutic cells nanometers medicament
.
In particular, due to its anti-inflammatory action, the MSC-derived EXOS (MSC-EXOS) have therapeutic autoimmune potential diseases, including atopic dermatitis, diabetes and Alzheimer's disease
.
In addition, they also show the potential to treat osteoarthritis by inducing polarization of M1-M2 macrophages in inflamed tissues
.
Although cancer-derived EXOS has the ability to affect the balance of M1-M2, they are not considered as therapeutic nano- drugs due to their tumorigenicity in the body
.
In general, for the treatment of rheumatoid arthritis, the need to develop an engineered MSC-EXOS that can effectively regulate the balance of macrophages M1-M2 has not yet been met
.

The clinical application of EXOS has been limited because most of them accumulate and clear in the liver and spleen, resulting in a short biological half-life in the body (<6 hours) after systemic administration
.
Generally speaking, the surface of exosomes has been modified based on genetic manipulation or chemical modification to overcome their poor distribution in the body
.
However, the former is not suitable for MSC-EXOS, and the complicated purification steps of the latter have caused concerns about low yield and dysfunction of extracellular bodies
.
Therefore, in order to develop a safer and more effective RA treatment based on MSC-EXOS, an effective surface editing strategy is essential without sacrificing its inherent biological function and/or yield
.
Here, the author reports the use of fat sourcesMetabolic sugar engineering (Mge) of stem cells (Adscs) performs fine surface editing of msc-exos to target activated macrophages in RA inflammatory joints
.
These EXOS replicate the natural inflammation subsidence in the lesion through M1-M2 polarization, providing a more solid foundation for RA treatment, and vice versa
.

Schematic diagram of DS-EXOS as a cell-free treatment system for rheumatoid arthritis

Image source: https://pubmed.
ncbi.
nlm.
nih.
gov/34078596/

In summary, in order to enhance the ability to target inflamed joints, the authors developed DS-EXOS using MGE-mediated click chemistry of ADSCs
.
This novel surface engineering strategy can be used to introduce a wide range of targeting moieties on MSC-EXOS without causing dysfunction in its structure or function
.
The targeted delivery of MSC-EXOS obtained from metabolically engineered stem cells provides a new cell-free treatment system for RA.
The resulting regulation of macrophage heterogeneity can be extended to various macrophage-related Diseases such as inflammatory bowel disease, idiopathic pulmonary fibrosis, atherosclerosis, and Alzheimer's disease
.
In addition to non- stem cell therapy, the study's findings have broad implications for the treatment of various types of cells derived EXOS treatment of refractory disease
.
( Bioon.
com)

Reference

Dong Gil You et al.
Metabolically engineered stem cell-derived exosomes to regulate macrophage heterogeneity in rheumatoid arthritis.
Sci Adv.
2021 Jun 2; 7(23): eabe0083.
doi: 10.
1126/sciadv.
Abe 0083.
Print 2021 Jun.