Browsing by Subject "Mesenchymal stem cell"

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    Intracerebroventricular injection of human umbilical cord blood mesenchymal stem cells in patients with Alzheimer’s disease dementia: a phase I clinical trial
    (BMC, 2021-09-14) Kim, Hee Jin; Cho, Kyung Rae; Jang, Hyemin; Lee, Na Kyung; Jung, Young Hee; Kim, Jun Pyo; Lee, Jung Il; Chang, Jong Wook; Park, Seongbeom; Kim, Sung Tae; Moon, Seung Whan; Seo, Sang Won; Choi, Soo Jin; Na, Duk L.; Radiology and Imaging Sciences, School of Medicine
    Backgrounds: Alzheimer's disease is the most common cause of dementia, and currently, there is no disease-modifying treatment. Favorable functional outcomes and reduction of amyloid levels were observed following transplantation of mesenchymal stem cells (MSCs) in animal studies. Objectives: We conducted a phase I clinical trial in nine patients with mild-to-moderate Alzheimer's disease dementia to evaluate the safety and dose-limiting toxicity of three repeated intracerebroventricular injections of human umbilical cord blood-derived MSCs (hUCB-MSCs). Methods: We recruited nine mild-to-moderate Alzheimer's disease dementia patients from Samsung Medical Center, Seoul, Republic of Korea. Four weeks prior to MSC administration, the Ommaya reservoir was implanted into the right lateral ventricle of the patients. Three patients received a low dose (1.0 × 107 cells/2 mL), and six patients received a high dose (3.0 × 107 cells/2 mL) of hUCB-MSCs. Three repeated injections of MSCs were performed (4-week intervals) in all nine patients. These patients were followed up to 12 weeks after the first hUCB-MSC injection and an additional 36 months in the extended observation study. Results: After hUCB-MSC injection, the most common adverse event was fever (n = 9) followed by headache (n = 7), nausea (n = 5), and vomiting (n = 4), which all subsided within 36 h. There were three serious adverse events in two participants that were considered to have arisen from the investigational product. Fever in a low dose participant and nausea with vomiting in another low dose participant each required extended hospitalization by a day. There were no dose-limiting toxicities. Five participants completed the 36-month extended observation study, and no further serious adverse events were observed. Conclusions: Three repeated administrations of hUCB-MSCs into the lateral ventricle via an Ommaya reservoir were feasible, relatively and sufficiently safe, and well-tolerated. Currently, we are undergoing an extended follow-up study for those who participated in a phase IIa trial where upon completion, we hope to gain a deeper understanding of the clinical efficacy of MSC AD therapy.
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    Lysosomal acid lipase in mesenchymal stem cell stimulation of tumor growth and metastasis
    (Impact Journals, 2016-09-20) Zhao, Ting; Yan, Cong; Du, Hong; Department of Pathology and Laboratory Medicine, IU School of Medicine
    Bone marrow mesenchymal stem cells (MSCs) are an important participant in the tumor microenvironment, in which they promote tumor growth and progression. Here we report for the first time that depletion of lysosomal acid lipase (LAL) in MSCs impairs their abilities to stimulate tumor growth and metastasis both in allogeneic and syngeneic mouse models. Reduced cell viability was observed in LAL-deficient (lal-/-) MSCs, which was a result of both increased apoptosis and decreased proliferation due to cell cycle arrest. The synthesis and secretion of cytokines and chemokines that are known to mediate MSCs' tumor-stimulating and immunosuppressive effects, i.e., IL-6, MCP-1 and IL-10, were down-regulated in lal-/- MSCs. When tumor cells were treated with the conditioned medium from lal-/- MSCs, decreased proliferation was observed, accompanied by reduced activation of oncogenic intracellular signaling molecules in tumor cells. Co-injection of lal-/- MSCs and B16 melanoma cells into wild type mice not only induced CD8+ cytotoxic T cells, but also decreased accumulation of tumor-promoting Ly6G+CD11b+ myeloid-derived suppressor cells (MDSCs), which may synergistically contribute to the impairment of tumor progression. Furthermore, lal-/- MSCs showed impaired differentiation towards tumor-associated fibroblasts. In addition, MDSCs facilitated MSC proliferation, which was mediated by MDSC-secreted cytokines and chemokines. Our results indicate that LAL plays a critical role in regulating MSCs' ability to stimulate tumor growth and metastasis, which provides a mechanistic basis for targeting LAL in MSCs to reduce the risk of cancer metastasis.
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    Mesenchymal stem cells protect against obstruction-induced renal fibrosis by decreasing STAT3 activation and STAT3-dependent MMP-9 production
    (American Physiological Society, 2017-01-01) Matsui, Futoshi; Babitz, Stephen A.; Rhee, Audrey; Hile, Karen L.; Zhang, Hongji; Meldrum, Kirstan K.; Urology, School of Medicine
    STAT3 is a transcription factor implicated in renal fibrotic injury, but the role of STAT3 in mesenchymal stem cell (MSC)-induced renoprotection during renal fibrosis remains unknown. We hypothesized that MSCs protect against obstruction-induced renal fibrosis by downregulating STAT3 activation and STAT3-induced matrix metalloproteinase-9 (MMP-9) expression. Male Sprague-Dawley rats underwent renal arterial injection of vehicle or MSCs (1 × 106/rat) immediately before sham operation or induction of unilateral ureteral obstruction (UUO). The kidneys were harvested after 4 wk and analyzed for collagen I and III gene expression, collagen deposition (Masson's trichrome), fibronectin, α-smooth muscle actin, active STAT3 (p-STAT3), MMP-9, and tissue inhibitor of matrix metalloproteinases 1 (TIMP-1) expression. In a separate arm, the STAT3 inhibitor S3I-201 (10 mg/kg) vs. vehicle was administered to rats intraperitoneally just after induction of UUO and daily for 14 days thereafter. The kidneys were harvested after 2 wk and analyzed for p-STAT3 and MMP-9 expression, and collagen and fibronectin deposition. Renal obstruction induced a significant increase in collagen, fibronectin, α-SMA, p-STAT3, MMP-9, and TIMP-1 expression while exogenously administered MSCs significantly reduced these indicators of obstruction-induced renal fibrosis. STAT3 inhibition with S3I-201 significantly reduced obstruction-induced MMP-9 expression and tubulointerstitial fibrosis. These results demonstrate that MSCs protect against obstruction-induced renal fibrosis, in part, by decreasing STAT3 activation and STAT3-dependent MMP-9 production.
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    Unraveling the Mechanistic Basis of Mesenchymal Stem Cell Activity in the Heart
    (Elsevier, 2006-12-01) Field, Loren J.; Pediatrics, School of Medicine