Sepsis is a deadly condition lacking a specific treatment despite decades of research. This has prompted the exploration of new approaches, with extracellular vesicles (EVs) emerging as a focal area. EVs are nanosized, cell‐derived particles that transport bioactive components (i.e., proteins, DNA, and RNA) between cells, enabling both normal physiological functions and disease progression depending on context. In particular, EVs have been identified as critical mediators of sepsis pathophysiology. However, EVs are also thought to constitute the biologically active component of cell‐based therapies and have demonstrated anti‐inflammatory, anti‐apoptotic, and immunomodulatory effects in sepsis models. The dual nature of EVs in sepsis is explored here, discussing their endogenous roles and highlighting their therapeutic properties and potential. Related to the latter component, prior studies involving EVs from mesenchymal stem/stromal cells (MSCs) and other sources are discussed and emerging producer cells that could play important roles in future EV‐based sepsis therapies are identified. Further, how methodologies could impact therapeutic development toward sepsis treatment to enhance and control EV potency is described.
Mesenchymal stromal cells expressing a dominant-negative high mobility group A1 transgene exhibit improved function during sepsis
High mobility group (HMG)A proteins are nonhistone chromatin proteins that bind to the minor groove of DNA, interact with transcriptional machinery, and facilitate DNA-directed nuclear processes. HMGA1 has been shown to regulate genes involved with systemic inflammatory processes. We hypothesized that HMGA1 is important in the function of mesenchymal stromal cells (MSCs), which are known to modulate inflammatory responses due to sepsis. To study this process, we harvested MSCs from transgenic (Tg) mice expressing a dominant-negative (dn) form of HMGA1 in mesenchymal cells. MSCs harvested from Tg mice contained the dnHMGA1 transgene, and transgene expression did not change endogenous HMGA1 levels. Immunophenotyping of the cells, along with trilineage differentiation revealed no striking differences between Tg and wild-type (WT) MSCs. However, Tg MSCs growth was decreased compared with WT MSCs, although Tg MSCs were more resistant to oxidative stress-induced death and expressed less IL-6. Tg MSCs administered after the onset of Escherichia coli-induced sepsis maintained their ability to improve survival when given in a single dose, in contrast with WT MSCs. This survival benefit of Tg MSCs was associated with less tissue cell death, and also a reduction in tissue neutrophil infiltration and expression of neutrophil chemokines. Finally, Tg MSCs promoted bacterial clearance and enhanced neutrophil phagocytosis, in part through their increased expression of stromal cell-derived factor-1 compared with WT MSCs. Taken together, these data demonstrate that expression of dnHMGA1 in MSCs provides a functional advantage of the cells when administered during bacterial sepsis.
more » « less- NSF-PAR ID:
- 10389522
- Publisher / Repository:
- Oxford University Press
- Date Published:
- Journal Name:
- Journal of Leukocyte Biology
- Volume:
- 110
- Issue:
- 4
- ISSN:
- 0741-5400
- Format(s):
- Medium: X Size: p. 711-722
- Size(s):
- ["p. 711-722"]
- Sponsoring Org:
- National Science Foundation
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