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Phase I clinical study of liver regenerative therapy for cirrhosis by intrahepatic arterial infusion of freshly isolated autologous adipose tissue-derived stromal/stem (regenerative) cell.

ABSTRACT: Introduction:Adipose tissue stromal cells contain a substantial number of mesenchymal stem cells. As such, their application to regeneration of miscellaneous impaired organs has attracted much attention. Methods:We designed a clinical study to investigate freshly isolated autologous adipose tissue-derived stromal/stem (regenerative) cell (ADRC) therapy for liver cirrhosis and conducted treatment in four cirrhotic patients. ADRCs were isolated from autologous subcutaneous adipose tissue obtained by the liposuction method, followed with use of the Celution system adipose tissue dissociation device. The primary endpoint is assessment of safety one month after treatment. We also characterized the obtained ADRCs. Results:Two patients had type C cirrhosis, one had nonalcoholic steatohepatitis-cirrhosis, and one had type B cirrhosis. No serious adverse events were observed during the 1-month study period after freshly isolated ADRC infusion. Serum albumin concentrations were maintained or improved during this period as well as during the succeeding follow-up of approximately 1 year in two patients and 6 months in another patient. Liver regeneration-related factors, namely hepatocyte growth factor and interleukin-6, were elevated 1 day after ADRC treatment in all patients. The obtained freshly isolated ADRCs were expanded in culture and found to express mesenchymal stem cell markers. Gene expression profile analysis of ADRCs was shown to involve inflammatory features, suggesting that characteristics of the obtained ADRCs were related to immunomodulatory biological effects. Conclusion:This clinical study treatment for liver cirrhosis using ADRCs was proven to be safely conductible, and can be further investigated in future for regeneration/repair of liver cirrhosis.

SUBMITTER: Sakai Y

PROVIDER: S-EPMC6134901 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Phase I clinical study of liver regenerative therapy for cirrhosis by intrahepatic arterial infusion of freshly isolated autologous adipose tissue-derived stromal/stem (regenerative) cell.

Sakai Yoshio Y Takamura Masayuki M Seki Akihiro A Sunagozaka Hajime H Terashima Takeshi T Komura Takuya T Yamato Masatoshi M Miyazawa Masaki M Kawaguchi Kazunori K Nasti Alessandro A Mochida Hatsune H Usui Soichiro S Otani Nobuhisa N Ochiya Takahiro T Wada Takashi T Honda Masao M Kaneko Shuichi S

Regenerative therapy 20170309

<h4>Introduction</h4>Adipose tissue stromal cells contain a substantial number of mesenchymal stem cells. As such, their application to regeneration of miscellaneous impaired organs has attracted much attention.<h4>Methods</h4>We designed a clinical study to investigate freshly isolated autologous adipose tissue-derived stromal/stem (regenerative) cell (ADRC) therapy for liver cirrhosis and conducted treatment in four cirrhotic patients. ADRCs were isolated from autologous subcutaneous adipose t ...[more]

PMID: 30271839

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Project description:: In patients undergoing maxillary sinus floor elevation (MSFE) for dental implant placement, bone substitutes are currently evaluated as alternatives for autologous bone. However, bone substitutes have only osteoconductive properties and lack osteoinductive potential. Therefore, this phase I study evaluated the potential additive effect on bone regeneration by the addition of freshly isolated, autologous but heterologous stromal vascular fraction (SVF), which is highly enriched with adipose stromal/stem cells when compared with native adipose tissue. From 10 patients, SVF was procured using automatic processing, seeded on either β-tricalcium phosphate (n = 5) or biphasic calcium phosphate carriers (n = 5), and used for MSFE in a one-step surgical procedure. Primary objectives were feasibility and safety. The secondary objective was efficacy, evaluated by using biopsies of the augmented area taken 6 months postoperatively, concomitant with dental implant placement. Biopsies were assessed for bone, graft, and osteoid volumes. No adverse effects were reported during the procedure or follow-up (≥3 years). Bone and osteoid percentages were higher in study biopsies (SVF supplemented) than in control biopsies (ceramic only on contralateral side), in particular in β-tricalcium phosphate-treated patients. Paired analysis on the six bilaterally treated patients revealed markedly higher bone and osteoid volumes using microcomputed tomography or histomorphometric evaluations, demonstrating an additive effect of SVF supplementation, independent of the bone substitute. This study demonstrated for the first time the feasibility, safety, and potential efficacy of SVF seeded on bone substitutes for MSFE, providing the first step toward a novel treatment concept that might offer broad potential for SVF-based regenerative medicine applications.SignificanceThis is the first-in-human study using freshly isolated, autologous adipose stem cell preparations (the stromal vascular fraction [SVF] of adipose tissue) applied in a one-step surgical procedure with calcium phosphate ceramics (CaP) to increase maxillary bone height for dental implantations. All 10 patients received CaP plus SVF on one side, whereas bilaterally treated patients (6 of 10) received CaP only on the opposite side. This allowed intrapatient evaluation of the potential added value of SVF supplementation, assessed in biopsies obtained after 6 months. Feasibility, safety, and potential efficacy of SVF for bone regeneration were demonstrated, showing high potential for this novel concept.

Project description:The acute respiratory distress syndrome (ARDS), affects up to 150,000 patients per year in the United States. We and other groups have demonstrated that bone marrow derived mesenchymal stromal stem cells prevent ARDS induced by systemic and local administration of endotoxin (lipopolysaccharide (LPS)) in mice.A study was undertaken to determine the effects of the diverse populations of bone marrow derived cells on the pathophysiology of ARDS, using a unique ex-vivo swine preparation, in which only the ventilated lung and the liver are perfused with autologous blood. Six experimental groups were designated as: 1) endotoxin alone, 2) endotoxin + total fresh whole bone marrow nuclear cells (BMC), 3) endotoxin + non-hematopoietic bone marrow cells (CD45 neg), 4) endotoxin + hematopoietic bone marrow cells (CD45 positive), 5) endotoxin + buffy coat and 6) endotoxin + in vitro expanded swine CD45 negative adherent allogeneic bone marrow cells (cultured CD45neg). We measured at different levels the biological consequences of the infusion of the different subsets of cells. The measured parameters were: pulmonary vascular resistance (PVR), gas exchange (PO2), lung edema (lung wet/dry weight), gene expression and serum concentrations of the pro-inflammatory cytokines IL-1?, TNF-? and IL-6.Infusion of freshly purified autologous total BMCs, as well as non-hematopoietic CD45(-) bone marrow cells significantly reduced endotoxin-induced pulmonary hypertension and hypoxemia and reduced the lung edema. Also, in the groups that received BMCs and cultured CD45neg we observed a decrease in the levels of IL-1? and TNF-? in plasma. Infusion of hematopoietic CD45(+) bone marrow cells or peripheral blood buffy coat cells did not protect against LPS-induced lung injury.We conclude that infusion of freshly isolated autologous whole bone marrow cells and the subset of non-hematopoietic cells can suppress the acute humoral and physiologic responses induced by endotoxemia by modulating the inflammatory response, mechanisms that do not involve engraftment or trans-differentiation of the cells. These observations may have important implications for the design of future cell therapies for ARDS.

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Phase I clinical study of liver regenerative therapy for cirrhosis by intrahepatic arterial infusion of freshly isolated autologous adipose tissue-derived stromal/stem (regenerative) cell.

Publications

Phase I clinical study of liver regenerative therapy for cirrhosis by intrahepatic arterial infusion of freshly isolated autologous adipose tissue-derived stromal/stem (regenerative) cell.

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