Conditioned Medium From Mesenchymal Stem Cells Enhances Early Bone Regeneration After Maxillary Sinus Floor Elevation in Rabbits

Katagiri, Wataru; Osugi, Masashi; Kinoshita, K; Hibi, Hideharu

doi:10.1097/id.0000000000000335

Cited by 28 publications

(32 citation statements)

References 20 publications

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“…A PLGA membrane with incorporated MSC‐CM promoted modest, but significantly higher bone formation compared to biomaterial controls in rat calvaria defects [ 220 ] and β‐TCP soaked with MSC‐CM led to earlier angiogenesis and bone regeneration in a sinus floor elevation rabbit model, but no overall increase in bone formation at 8 weeks. [ 221 ] Recent research which employed EVs isolated from MSC‐CM suggests therapeutic potential of EV‐functionalized biomaterials for bone repair. EV‐loaded β‐TCP scaffolds promoted bone regeneration in critical‐sized rat calvaria defects in a dose‐dependent manner, with EV‐mediated osteogenic differentiation mediated through activation of the PI3K/Akt signaling pathway.…”

Section: Biomaterials Functionalized With Msc Secretomementioning

confidence: 99%

Biomaterials Functionalized with MSC Secreted Extracellular Vesicles and Soluble Factors for Tissue Regeneration

Brennan

Layrolle

Mooney

2020

Adv Funct Materials

236

196

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The therapeutic benefits of mesenchymal stromal cell (MSC) transplantation are attributed to their secreted factors, including extracellular vesicles (EVs) and soluble factors. The potential of employing the MSC secretome as an alternative acellular approach to cell therapy is being investigated in various tissue injury indications, but EVs administered via bolus injections are rapidly sequestered and cleared. However, biomaterials offer delivery platforms to enhance EV retention rates and healing efficacy. This review highlights the mechanisms underpinning the therapeutic effects of MSC‐EVs and soluble factors as effectors of immunomodulation and tissue regeneration, conferred primarily via their nucleic acid and protein contents. Discussed is how manipulating the cell culture microenvironment or genetic modification of MSCs can further augment the potency of their secretions. The most recent advances in the development of EV‐functionalized biomaterials that mediate enhanced angiogenesis and cell survival, while attenuating inflammation and fibrosis, are presented. Finally, some technical challenges to be considered for the clinical translation of biomaterials carrying MSC‐secreted bioactive cargo are discussed.

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Section: Biomaterials Functionalized With Msc Secretomementioning

confidence: 99%

Biomaterials Functionalized with MSC Secreted Extracellular Vesicles and Soluble Factors for Tissue Regeneration

Brennan

Layrolle

Mooney

2020

Adv Funct Materials

236

196

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“…The therapeutic effects of mesenchymal stem cell‐conditioned media have been explored in other diseases, such as ischemic heart disease, brain injury, spinal cord injury and bone defects. The use of cell‐free therapies, such as conditioned media from mesenchymal stem cells, has specific advantages over stem cell‐based therapies.…”

Section: Discussionmentioning

confidence: 99%

Conditioned media from dental pulp stem cells improved diabetic polyneuropathy through anti‐inflammatory, neuroprotective and angiogenic actions: Cell‐free regenerative medicine for diabetic polyneuropathy

Makino

Nakamura

Miyabe

et al. 2019

J of Diabetes Invest

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Aims/Introduction Dental pulp stem cells (DPSCs) can be easily obtained from teeth for general orthodontic reasons. We have previously reported the therapeutic effects of DPSC transplantation for diabetic polyneuropathy. As abundant secretomes from DPSCs are considered to play a central role in the improvement of diabetic polyneuropathy, we investigated whether direct injection of DPSC‐conditioned media (DPSC‐CM) into hindlimb skeletal muscles ameliorates diabetic polyneuropathy in diabetic rats. Materials and Methods DPSCs were isolated from the dental pulp of Sprague–Dawley rats. Eight weeks after the induction of diabetes, DPSC‐CM was injected into the unilateral hindlimb skeletal muscles in both normal and diabetic rats. The effects of DPSC‐CM on diabetic polyneuropathy were assessed 4 weeks after DPSC‐CM injection. To confirm the angiogenic effect of DPSC‐CM, the effect of DPSC‐CM on cultured human umbilical vascular endothelial cell proliferation was investigated. Results The administration of DPSC‐CM into the hindlimb skeletal muscles significantly ameliorated sciatic motor/sensory nerve conduction velocity, sciatic nerve blood flow and intraepidermal nerve fiber density in the footpads of diabetic rats. We also showed that DPSC‐CM injection significantly increased the capillary density of the skeletal muscles, and suppressed pro‐inflammatory reactions in the sciatic nerves of diabetic rats. Furthermore, an in vitro study showed that DPSC‐CM significantly increased the proliferation of umbilical vascular endothelial cells. Conclusions We showed that DPSC‐CM injection into hindlimb skeletal muscles has a therapeutic effect on diabetic polyneuropathy through neuroprotective, angiogenic and anti‐inflammatory actions. DPSC‐CM could be a novel cell‐free regenerative medicine treatment for diabetic polyneuropathy.

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“…We have reported that MSC-CM contains cytokines such as IGF-1, VEGF, and TGF-β1, which may synergistically affect migration, angiogenesis, and osteogenic differentiation of host MSCs [5, 6, 9, 10]. The effects of these three cytokines are thought to be very complex, although IGF-1 is believed to regulate the migration of osteoblasts [20] and MSCs [21], and sustained systemic or local infusion of IGF-1 was shown to enhance bone formation [22], while TGF-β1 stimulates migration of osteoprogenitor cells and regulates cellular proliferation, differentiation, and production of extracellular matrix [23].…”

Section: Discussionmentioning

confidence: 99%

“…These secretomes will be released from the implanted cells and will establish a new blood supply via migration of endothelial cells to the sites of bone defects and subsequent angiogenesis. Our previous study reported that MSC-CM enhanced the migration of MSCs, tube formation of human umbilical vein endothelial cells (HUVECs), expression of osteogenic and angiogenic markers of MSCs in vitro, and bone and periodontal regeneration in vivo [8–10]. We hypothesized that angiogenesis is an important step for bone regeneration and that VEGF is a crucial factor in MSC-CM that enhances its osteogenic potential.…”

Section: Introductionmentioning

confidence: 99%

Angiogenesis in newly regenerated bone by secretomes of human mesenchymal stem cells

Katagiri

Kawai

Osugi

et al. 2017

Maxillofac Plast Reconstr Surg

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BackgroundFor an effective bone graft for reconstruction of the maxillofacial region, an adequate vascular network will be required to supply blood, osteoprogenitor cells, and growth factors. We previously reported that the secretomes of bone marrow-derived mesenchymal stem cells (MSC-CM) contain numerous growth factors such as insulin-like growth factor (IGF)-1, transforming growth factor (TGF)-β1, and vascular endothelial growth factor (VEGF), which can affect the cellular characteristics and behavior of regenerating bone cells. We hypothesized that angiogenesis is an important step for bone regeneration, and VEGF is one of the crucial factors in MSC-CM that would enhance its osteogenic potential. In the present study, we focused on VEGF in MSC-CM and evaluated the angiogenic and osteogenic potentials of MSC-CM for bone regeneration.MethodsCytokines in MSC-CM were measured by enzyme-linked immunosorbent assay (ELISA). Human umbilical vein endothelial cells (HUVECs) were cultured with MSC-CM or MSC-CM with anti-VEGF antibody (MSC-CM + anti-VEGF) for neutralization, and tube formation was evaluated. For the evaluation of bone and blood vessel formation with micro-computed tomography (micro-CT) and for the histological and immunohistochemical analyses, a rat calvarial bone defect model was used.ResultsThe concentrations of IGF-1, VEGF, and TGF-β1 in MSC-CM were 1515.6 ± 211.8 pg/mL, 465.8 ± 108.8 pg/mL, and 339.8 ± 14.4 pg/mL, respectively. Tube formation of HUVECs, bone formation, and blood vessel formation were increased in the MSC-CM group but decreased in the MSC-CM + anti-VEGF group. Histological findings suggested that new bone formation in the entire defect was observed in the MSC-CM group although it was decreased in the MSC-CM + anti-VEGF group. Immunohistochemistry indicated that angiogenesis and migration of endogenous stem cells were much more abundant in the MSC-CM group than in the MSC-CM + anti-VEGF group.ConclusionsVEGF is considered a crucial factor in MSC-CM, and MSC-CM is proposed to be an adequate therapeutic agent for bone regeneration with angiogenesis.

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Conditioned Medium From Mesenchymal Stem Cells Enhances Early Bone Regeneration After Maxillary Sinus Floor Elevation in Rabbits

Abstract: MSC-CM is a promising novel therapeutic agent to promote bone regeneration after maxillary sinus floor elevation.

Cited by 28 publications

References 20 publications

Biomaterials Functionalized with MSC Secreted Extracellular Vesicles and Soluble Factors for Tissue Regeneration

Biomaterials Functionalized with MSC Secreted Extracellular Vesicles and Soluble Factors for Tissue Regeneration

Conditioned media from dental pulp stem cells improved diabetic polyneuropathy through anti‐inflammatory, neuroprotective and angiogenic actions: Cell‐free regenerative medicine for diabetic polyneuropathy

Angiogenesis in newly regenerated bone by secretomes of human mesenchymal stem cells

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