Immunoregulatory role of exosomes derived from differentiating mesenchymal stromal cells on inflammation and osteogenesis

Abstract

Bone marrow-derived mesenchymal stem/stromal cells (BMSCs) can differentiate into bone-forming osteoblasts, playing a crucial role in bone regeneration. Exosomes are naturally cell-secreted nanovesicles and are lately regraded as an emerging mediator of cellular communication in physiological and pathological conditions. The present study aimed at investigating the complex cellular communications, especially those among the differentiating BMSCs, immune cells (e.g., macrophages), and newly recruited BMSCs via exosome-mediated pathways. Exosomes were first isolated from osteogenically differentiating BMSCs at various stages (Day 0, Day 3, Day 7, and Day 14, respectively). The cellular uptake of isolated exosomes was examined in macrophages and human BMSCs (hBMSCs). The exosomes collected at various osteogenic differentiation stages (0d-exo, 3d-exo, 7d-exo, and 14d-exo) had no effect on the viability of hBMSCs. The uptake of exosomes (0d-exo, 3d-exo, and 7d-exo) significantly decreased proinflammatory-gene expression and the level of an M1 phenotypic marker. Our results then revealed that 3d-exo, 7d-exo, and 14d-exo led to a remarkable increase in mesenchymal stem/stromal cell migration. In addition, 0d-exo significantly promoted the expression of early osteogenic markers, such as alkaline phosphatase and bone morphogenetic protein 2, indicating a pro-osteogenic role of hBMSC-derived exosomes. Collectively, these results suggest that exosomes derived from differentiating mesenchymal stem/stromal cells play a unique osteoimmunomodulatory role in the regulation of bone dynamics.

Umbilical cord-derived Wharton’s jelly for regenerative medicine applications

“…They positively affect cell proliferation and viability, angiogenesis, and immunomodulation in different physiological systems [47]. Exosome uptake by cells significantly reduces pro-inflammatory gene expression and level of M1 phenotypic marker, increase cell migration, and increase expression of osteogenic markers, which play a unique osteo-immunomodulatory role in regulation of bone dynamics [48]. Exosomes stimulate secretion of favorable cellular factors required to accelerate the healing response for tendon injuries including rotator cuff tears [49,50].…”

Immunomodulatory Effects of MSCs in Bone Healing

“…However, the continuous or abnormal boosting of immune cells or releasing of pro-inflammatory molecules is detrimental to the process of bone regeneration [3]. Through the proliferation phase, re-epithelialization, angiogenesis, collagen synthesis and extracellular matrix (ECM) formation take place, and, finally in the remodeling phase, collagen deposition as well as vascular maturation and regression occur [4]. In bone healing under unimpaired conditions, the immunomodulatory effect of MSCs could be crucial for establishing novel therapeutic strategies to ameliorate inefficient bone remodeling.…”

<p>Neuroprotective Effect of Mesenchymal Stromal Cell-Derived Extracellular Vesicles Against Cerebral Ischemia-Reperfusion-Induced Neural Functional Injury: A Pivotal Role for AMPK and JAK2/STAT3/NF-κB Signaling Pathway Modulation</p>

“…as previously described. 32 In brief, 5 μL of extracted MSCs-EVs in PBS was deposited onto carbon/formvarcoated Cu TEM grids and then dried for 10 min at 40°C before staining with 1% uranyl acetate for 20 s. The grids were washed twice in deionized water and dried on Whatman filter paper. Then, MSCs-EVs were imaged by TEM at 80 kV and then air-dried for 20 min.…”