Page 463 - IJB-9-2

International Journal of Bioprinting Bioprinting of exosomes

2. Exosomes as cell modulators in osteogenic differentiation of MSCs by inhibiting bone
regenerative medicine morphogenetic protein (BMP) 2, BMP9, and runt-related
transcription factor 2 (RUNX2) expressions, while EXOs
The therapeutic potential of cell-derived EXOs, which from M2 macrophages increased osteoconductive gene
includes their anti-inflammatory, immunosuppressive, expression in MSCs compared to controls . Along
[32]
pro/anti-angiogenic, and anti-fibrotic properties, has been similar lines, M2 macrophage-derived EXOs which are
actively exploited for various applications of regenerative rich in miR-501 have been found to promote myotube
medicine . For example, Zhang et al. demonstrated that formation in C2C12 cells in vitro and pubococcygeal
[13]
EXOs can promote the proliferation of dermal fibroblasts muscle regeneration in a stress urinary incontinence
and epidermal keratinocytes, inhibit apoptosis, and activate animal model in vivo . Additionally, EXOs from M2
[33]
the protein kinase B (Akt) pathway to promote cutaneous macrophages enriched with miR-590-3p have been found
wound healing through a rat skin burn model . Shabbir to promote colonic epithelial cell proliferation in a dose-
[25]
et al. showed that MSC-EXOs enhanced the migration dependent manner in vitro and improve the wound-
of normal adult fibroblasts and diabetic chronic wound healing ability of epithelial cells upon administration in
fibroblasts, isolated from a diabetic patient with non- a dextran saline sulfate-induced colitis murine model
healing ulcer, in vitro . EXOs have been found to induce in vivo . Likewise, EXOs from B cells have been shown
[26]
[34]
angiogenesis and activate several key signaling pathways, to regulate bone homeostasis during fracture healing by
such as Akt, STAT3, and ERK, which are known to induce the inhibiting excessive osteogenic activity in a mouse fracture
expression of various growth factors, including hepatocyte model . There is also evidence showing that EXOs
[35]
growth factor, insulin growth factor 1, nerve growth factor, released from dendritic cells (DCs) and regulatory T cells
and stromal cell-derived factor 1, all of which are conducive play a crucial role in exerting cardioprotective effects
for wound healing and tissue regeneration . In a similar following MI [36-39] . Another study found that EXOs secreted
[26]
study, Geiger et al. demonstrated that fibrocyte-derived from DC mediated CD4 T-cell activation and improved
+
EXOs exhibited pro-angiogenic properties and induced cardiac function in mice post MI . Along similar lines,
[36]
the migration and proliferation of diabetic keratinocytes EXOs produced by regulatory T cells have been found to
to accelerate wound closure in diabetic mice in vivo . inhibit the proinflammatory function of effector T cells ,
[27]
[35]
Additionally, miRNAs present in secreted EXOs have been induce a tolerogenic phenotype in DCs , and promote
[38]
shown to exert cardioprotective effects by enhancing the M2 macrophage polarization , thereby fostering a
[39]
functionality of cardiomyocytes, preventing fibrosis, and microenvironment conducive for cardiac repair and
promoting angiogenesis in ischemic cardiac muscles after regeneration. Furthermore, EXOs released from dendritic
myocardial infarction (MI) . Wang et al. showed that epidermal T cells, which are T cells in the skin that possess
[28]
subretinal delivery of retinal pigment epithelium-derived a dendritic-like shape, have been found to promote the
EXOs ameliorated photoreceptor loss and enhanced proliferation of epidermal stem cells and accelerate wound
visual responsiveness in an N-methyl-N-nitrosourea- re-epithelialization in a murine excision wound injury
induced mouse model of retinal degeneration . Along model in vivo .
[29]
[40]
similar lines, Yu et al. demonstrated that the intravitreal
administration of MSC-derived EXOs inhibited apoptosis, There is a growing line of evidence showing that
suppressed inflammatory responses, and downregulated EXOs play an active role in extracellular matrix (ECM)
monocyte chemoattractant protein-1 (MCP-1) to improve remodeling and in directly influencing cell binding and
visual acuity and recovery in a laser-induced retinal injury migration into tissue matrix [41-43] . More specifically, it has
mouse model . Yet, another study revealed that the been demonstrated that cells continuously endocytose
[30]
intravenous administration of BMMSC EXOs in a focal ECM molecules and re-secrete them on the exofacial
cerebral ischemia mouse model improved neurological surface of EXOs , which confer unique ECM-modulating
[44]
functions through long-term neuroprotection and the properties to EXOs that can be exploited for orchestrating
induction of angiogenesis . tissue regeneration and wound healing. In regard to this,
[31]
several ECM molecules, including fibronectin (FN),
In addition to MSC-derived EXOs, there are mounting glycosaminoglycans (GAGs), proteoglycans (PGs),
data to suggest that EXOs produced by immune cells hyaluronic acid (HA), and enzymes, such as proteases
can also be availed for tissue regenerative applications. and glycosidases, have been identified on the exofacial
For instance, EXOs derived from polarized macrophage surface of EXOs [41,43] . Studies have shown that FN-coated
populations can be manipulated to negatively or positively EXOs, which are involved in the endocytosis of integrin
regulate bone regeneration . Particularly, EXOs released αvβ1–fibronectin complex, interact with heparan sulfate
[32]
from M1 macrophages have been shown to reduce (HS) PGs on the cell membrane to facilitate EXO uptake
[45]
Volume 9 Issue 2 (2023) 455 https://doi.org/10.18063/ijb.690