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Bonomi A.,University of Milan | Cocce V.,University of Milan | Cavicchini L.,University of Milan | Sisto F.,University of Milan | And 7 more authors.
International Journal of Immunopathology and Pharmacology | Year: 2013

Many strategies, including those based on genetically modified Mesenchymal Stromal Cells (MSCs), have been developed in recent years in order to obtain high concentrations of anticancer drugs effective on tumor mass. In previous studies, we showed that human and murine bone marrow-derived MSCs (BM-MSCs) and human skin-derived stromal fibroblasts (hSDFs) acquired strong anti-tumor capacity, both in vitro and in vivo, once primed with Paclitaxel (PTX). In this report we investigate whether adipose tissue-derived MSCs (AT-MSCs) behave similarly to BM-MSCs in their uptake and release of PTX in sufficient amounts to inhibit tumor proliferation in vitro. According to a standardized procedure, PTX primed AT-MSCs (AT-MSCsPTX) were washed and then subcultured to harvest their conditioned medium, which was then tested to evaluate its in vitro anti-tumor potential. We observed that AT-MSCsPTX were able to uptake PTX and release it in a time-dependent manner and that the released drug was active in vitro against proliferation of leukemia, anaplastic osteosarcoma, prostatic carcinoma and neuroblastoma cell lines. These data confirm that AT-MSCs, as well as BM-MSCs, can be loaded in vitro with anti-cancer drugs. While the harvesting of BM-MSCs requires invasive procedures, AT-MSCs can be prepared from fat samples taken with little patient discomfort. For this reason, this source of stromal cells represents an important alternative to BM-MSCs in developing new tools for carrying and delivering anti-cancer drugs into tumor microenvironments. © 2013 SAGE Publications.


Pessina A.,University of Milan | Cocce V.,University of Milan | Bonomi A.,University of Milan | Bonomi A.,Cellular Neurobiology Laboratory | And 10 more authors.
Anti-Cancer Agents in Medicinal Chemistry | Year: 2013

The main goal in cancer chemotherapy is to drive the drug into the tumor microenvironment to kill as many cancer cells as possible while producing the lowest collateral toxicity. Previously, we have shown that human bone marrow derived mesenchymal stromal cells (hBM-MSCs) exposed to Paclitaxel (PTX) were able to uptake and subsequently release the drug in the culture medium. PTX primed hBM-MSCs (hBM-MSCsPTX) located in the vicinity of cancer cells produced a strong inhibition of tumor cell growth both in vitro and in vivo. To expand these observations, in the present study we exposed human skin derived fibroblasts (hSDFs) to 2,000 ng/ml of PTX and then tested both cells and their conditioned medium (CM) in vitro for their capacity to inhibit the proliferation of human tumor cell lines (MOLT-4, DU-145, U87-MG, SH-SY5Y(+) and LAN-5). We found that hSDFs primed with PTX (hSDFsPTX) were able to uptake and subsequently release PTX in a time dependent manner. hSDFsPTX-derived CM(hSDFsPTX-CM) from 1:4 to 1:10 dilutions produced a significant (p<0.05) in vitro tumor growth inhibition. hSDFsPTX co-cultured with leukemia cells at 1:1 to 1:10 ratio, completely inhibited cells growth whereas no inhibition was induced by normal hSDFs cells. Our results demonstrate for the first time that hSDFs can be loaded in vitro with PTX and thus can acquire a potent anti-tumor activity. Since hSDFs can be easily isolated from skin biopsies without any particular pain and discomfort to donor patients, we conclude that hSDFs may represent a valid cell type option for carrying and delivering anti-cancer drugs. © 2013 Bentham Science Publishers.


Bonomi A.,University of Milan | Steimberg N.,University of Brescia | Benetti A.,University of Brescia | Berenzi A.,University of Brescia | And 7 more authors.
Hematological Oncology | Year: 2016

Multiple myeloma is an aggressive tumour able to suppress osteoblastogenesis probably mediated by bone marrow mesenchymal stromal cells (BM-MSCs) that can also support plasma cell growth/survival. The use of MSCs for multiple myeloma therapy is a controversial topic because of the contradictory results on the capacity of MSCs to inhibit or to promote cancer growth. Our previous studies demonstrated that MSCs could be loaded with Paclitaxel (PTX) and used to deliver the drug in situ in amount affecting tumour growth (in vitro and in vivo). Therefore, independently on the discussed action of MSCs in myeloma, MSCs could represent a 'trojan horse' to vehicle and deliver anti-tumour agents into bone marrow. This study confirms, by an in vitro 3D dynamic culture system, that PTX loaded BM-MSCs (PTXr-MSCs) are active on the proliferation of RPMI 8226, a human myeloma cell line. Our results demonstrated a dramatic suppression of myeloma cell growth by PTXr-MSCs, suggesting that drug loaded MSCs could be a tool to deliver drug into the bone marrow. Drug releasing MSCs provide a therapeutic approach to potentiate the existing treatments against a very aggressive malignancy as multiple myeloma. © 2016 John Wiley & Sons, Ltd.


Cunningham M.,Laboratory for Neural Reconstruction | Cho J.-H.,University of California at Riverside | Leung A.,Harvard Stem Cell Institute | Savvidis G.,Harvard Stem Cell Institute | And 8 more authors.
Cell Stem Cell | Year: 2014

Seizure disorders debilitate more than 65,000,000 people worldwide, with temporal lobe epilepsy (TLE) being the most common form. Previous studies have shown that transplantation of GABA-releasing cells results in suppression of seizures in epileptic mice. Derivation of interneurons from human pluripotent stem cells (hPSCs) has been reported, pointing to clinical translation of quality-controlled human cell sources that can enhance inhibitory drive and restore host circuitry. In this study, we demonstrate that hPSC-derived maturing GABAergic interneurons (mGINs) migrate extensively and integrate into dysfunctional circuitry of the epileptic mouse brain. Using optogenetic approaches, we find that grafted mGINs generate inhibitory postsynaptic responses in host hippocampal neurons. Importantly, even before acquiring full electrophysiological maturation, grafted neurons were capable of suppressing seizures and ameliorating behavioral abnormalities such as cognitive deficits, aggressiveness, and hyperactivity. These results provide support for the potential of hPSC-derived mGIN for restorative cell therapy for epilepsy. ©2014 Elsevier Inc.


News Article | November 13, 2015
Site: www.biosciencetechnology.com

Salk Institute researchers have found that an experimental drug candidate aimed at combating Alzheimer's disease has a host of unexpected anti-aging effects in animals. The Salk team expanded upon their previous development of a drug candidate, called J147, which takes a different tack by targeting Alzheimer's major risk factor--old age. In the new work, the team showed that the drug candidate worked well in a mouse model of aging not typically used in Alzheimer's research. When these mice were treated with J147, they had better memory and cognition, healthier blood vessels in the brain and other improved physiological features, as detailed November 12, 2015 in the journal Aging. "Initially, the impetus was to test this drug in a novel animal model that was more similar to 99 percent of Alzheimer's cases," said Antonio Currais, the lead author and a member of Professor David Schubert's Cellular Neurobiology Laboratory at Salk. "We did not predict we'd see this sort of anti-aging effect, but J147 made old mice look like they were young, based upon a number of physiological parameters." Alzheimer's disease is a progressive brain disorder, recently ranked as the third leading cause of death in the United States and affecting more than five million Americans. It is also the most common cause of dementia in older adults, according to the National Institutes of Health. "While most drugs developed in the past 20 years target the amyloid plaque deposits in the brain (which are a hallmark of the disease), none have proven effective in the clinic," said Schubert, senior author of the study. Several years ago, Schubert and his colleagues began to approach the treatment of the disease from a new angle. Rather than target amyloid, the lab decided to zero in on the major risk factor for the disease--old age. Using cell-based screens against old age-associated brain toxicities, they synthesized J147. Previously, the team found that J147 could prevent and even reverse memory loss and Alzheimer's pathology in mice that have a version of the inherited form of Alzheimer's, the most commonly used mouse model. However, this form of the disease comprises only about 1 percent of Alzheimer's cases. For everyone else, old age is the primary risk factor, said Schubert. The team wanted to explore the effects of the drug candidate on a breed of mice that age rapidly and experience a version of dementia that more closely resembles the age-related human disorder. In this latest work, the researchers used a comprehensive set of assaid to measure the expression of all genes in the brain, as well as over 500 small molecules involved with metabolism in the brains and blood of three groups of the rapidly aging mice. The three groups of rapidly aging mice included one set that was young, one set that was old and one set that was old but fed J147 as they aged. The old mice that received J147 performed better on memory and other tests for cognition and also displayed more robust motor movements. The mice treated with J147 also had fewer pathological signs of Alzheimer's in their brains. Importantly, because of the large amount of data collected on the three groups of mice, it was possible to demonstrate that many aspects of gene expression and metabolism in the old mice fed J147 were very similar to those of the young animals. These included markers for increased energy metabolism, reduced brain inflammation and reduced levels of oxidized fatty acids in the brain. Another notable effect was that J147 prevented the leakage of blood from the microvessels in the brains of old mice. "Damaged blood vessels are a common feature of aging in general, and in Alzheimer's, it is frequently much worse," said Currais. Currais and Schubert note that while these studies represent a new and exciting approach to Alzheimer's drug discovery and animal testing in the context of aging, the only way to demonstrate the clinical relevance of the work is to move J147 into human clinical trials for Alzheimer's disease. "If proven safe and effective for Alzheimer's, the apparent anti-aging effect of J147 would be a welcome benefit," adds Schubert. The team aims to begin human trials next year.

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