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Abstract
Achieving and maintaining safe and reliable lineage specific differentiation of stem
cells is important for clinical translation of tissue engineering strategies. In an
effort to circumvent the multitude of problems arising from the usage of growth factors
and growth factor delivery systems, we have explored the use of exosomes as biomimetic
tools to induce stem cell differentiation. Working on the hypothesis that cell-type
specific exosomes can trigger lineage-specific differentiation of stem cells, we have
evaluated the potential of exosomes derived from dental pulp cells cultured on under
growth and odontogenic differentiation conditions to induce odontogenic differentiation
of naïve human dental pulp stem cells (DPSCs) and human bone marrow derived stromal
cells (HMSCs) in vitro and in vivo. Results indicate that the exosomes can bind to
matrix proteins such as type I collagen and fibronectin enabling them to be tethered
to biomaterials. The exosomes are endocytosed by both DPSCs and HMSCs in a dose-dependent
and saturable manner via the caveolar endocytic mechanism and trigger the P38 mitogen
activated protein kinase (MAPK) pathway. In addition, the exosomes also trigger the
increased expression of genes required for odontogenic differentiation. When tested
in vivo in a tooth root slice model with DPSCs, the exosomes triggered regeneration
of dental pulp-like tissue. However, our results indicate that exosomes isolated under
odontogenic conditions are better inducers of stem cell differentiation and tissue
regeneration. Overall, our results highlight the potential exosomes as biomimetic
tools to induce lineage specific differentiation of stem cells. Our results also show
the importance of considering the source and state of exosome donor cells before a
choice is made for therapeutic applications.