Dormant breast cancers resurge as metastatic disease after a long dormancy period in the bone marrow, where cancer cells interact with mesenchymal stem cells (MSC). However, the nature of early interactions between breast cancer cells and MSCs in the bone marrow microenvironment that facilitate adaptation to a quiescent state remains poorly understood. Here, we report that breast cancer cells prime MSC to release exosomes containing distinct miRNA contents, such as miR-222/223, which in turn promotes quiescence in a subset of cancer cells and confers drug resistance. Building on these results, we developed a novel, nontoxic therapeutic strategy to target dormant breast cancer cells based on systemic administration of MSC loaded with antagomiR-222/223. In an immunodeficient mouse model of dormant breast cancer, this therapy sensitized breast cancer cells to carboplatin-based therapy and increased host survival. Overall, our findings illuminate the nature of the regulatory interactions between breast cancer cells and MSCs in the evolution of tumor dormancy and resurgence in the micrometastatic microenvironment of the bone marrow. Cancer Res; 76(19); 5832-44. ©2016 AACR.

/pdf/mesenchymal-stem-cell-derived-exosomes-stimulate-cycling-3lzieuht9i.pdf

Mesenchymal Stem Cell–Derived Exosomes Stimulate Cycling Quiescence and Early Breast Cancer Dormancy in Bone Marrow

https://escholarship.org/content/qt3ch3s275/qt3ch3s275.pdf?t=pud4bl

Human Mesenchymal Stem Cells Genetically Engineered to Overexpress Brain-derived Neurotrophic Factor Improve Outcomes in Huntington's Disease Mouse Models.

Cell encapsulation: Overcoming barriers in cell transplantation in diabetes and beyond.

The development of realistic in vitro blood–brain barrier (BBB) models that recapitulate the physiological parameters and molecular aspect of the neurovascular unit (NVU) is of fundamental importan...

https://journals.sagepub.com/doi/pdf/10.1177/0271678X18788769

In-vitro blood-brain barrier modeling: A review of modern and fast-advancing technologies.

Glioblastoma (GBM) is the most common primary brain tumor and carries a grave prognosis. Despite years of research investigating potentially new therapies for GBM, the median survival rate of individuals with this disease has remained fairly stagnant. Delivery of drugs to the tumor site is hampered by various barriers posed by the GBM pathological process and by the complex physiology of the blood-brain and blood–cerebrospinal fluid barriers. These anatomical and physiological barriers serve as a natural protection for the brain and preserve brain homeostasis, but they also have significantly limited the reach of intraparenchymal treatments in patients with GBM. In this article, the authors review the functional capabilities of the physical and physiological barriers that impede chemotherapy for GBM, with a specific focus on the pathological alterations of the blood-brain barrier (BBB) in this disease. They also provide an overview of current and future methods for circumventing these barriers in therapeu...

/pdf/novel-delivery-methods-bypassing-the-blood-brain-and-blood-3butulcf1u.pdf

Novel delivery methods bypassing the blood-brain and blood-tumor barriers.

The blood brain barrier (BBB) poses a problem to deliver drugs for brain malignancies and neurodegenerative disorders. Stem cells such as neural stem cells (NSCs) and mesenchymal stem cells (MSCs) can be used to delivery drugs or RNA to the brain. This use of methods to bypass the hurdles of delivering drugs across the BBB is particularly important for diseases with poor prognosis such as glioblastoma multiforme (GBM). Stem cell treatment to deliver drugs to neural tumors is currently in clinical trial. This method, albeit in the early phase, could be an advantage because stem cells can cross the BBB into the brain. MSCs are particularly interesting because to date, the experimental and clinical evidence showed ‘no alarm signal’ with regards to safety. Additionally, MSCs do not form tumors as other more primitive stem cells such as embryonic stem cells. More importantly, MSCs showed pathotropism by migrating to sites of tissue insult. Due to the ability of MSCs to be transplanted across allogeneic barrier, drug-engineered MSCs can be available as off-the-shelf cells for rapid transplantation. This review discusses the advantages and disadvantages of stem cells to deliver prodrugs, genes and RNA to treat neural disorders.

/pdf/stem-cell-delivery-of-therapies-for-brain-disorders-34turhh13l.pdf

Stem cell delivery of therapies for brain disorders

Anthrax receptor (ATR) shares similarities with molecules relevant to haematopoiesis. This suggests that anthrax proteins might bind to these mimicking molecules and exert non-specific haematopoietic effects. The haematopoietic system is the site of immune cell development in the adult. As such, ATR ligand, protective antigen (PA) and the other anthrax proteins, lethal factor, edema factor, could be significant to haematopoietic responses against Bacillus anthracis infection. Because haematopoiesis is the process of immune cell development, effects by anthrax proteins could be relevant to vaccine development. Here, we report on effects of anthrax proteins and toxins on early and late haematopoiesis. Flow cytometry shows binding of PA to haematopoietic cells. This binding might be partly specific because flow cytometry and Western blots demonstrate the presence of ATR1 on haematopoietic cell subsets and the supporting stromal cells. Functional studies with long-term initiating cell and clonogenic assays determined haematopoietic suppression by anthrax toxins and stimulation by monomeric proteins. The suppressive effects were not attributed to cell death, but partly through the induction of haematopoietic suppressors, interleukin (IL)-10 and CCL3 (MIP-1α). In summary, anthrax proteins affect immune cell development by effects on haematopoiesis. The type of effect, stimulation or suppression, depend on whether the stimulator is a toxin or monomeric protein. The studies show effects of anthrax proteins beginning at the early stage of haematopoiesis, and also show secondary mediators such as IL-10 and CCL3. The roles of other cytokines and additional ATR are yet to be investigated.

Non-canonical effects of anthrax toxins on haematopoiesis: implications for vaccine development.

Orthotopic liver transplant (OLT) remains the standard of care for end stage liver disease. To circumvent allo-rejection, OLT subjects receive gluococorticoids (GC). We investigated the effects of GC on endogenous mesenchymal stem (stromal) cells (MSCs) in OLT. This question is relevant because MSCs have regenerative potential and immune suppressor function. Phenotypic analyses of blood samples from 12 OLT recipients, at pre-anhepatic, anhepatic and post-transplant (2 h, Days 1 and 5) indicated a significant decrease in MSCs after GC injection. The MSCs showed better recovery in the blood from subjects who started with relatively low MSCs as compared to those with high levels at the prehepatic phase. This drop in MSCs appeared to be linked to GC since similar change was not observed in liver resection subjects. In order to understand the effects of GC on decrease MSC migration, in vitro studies were performed in transwell cultures. Untreated MSCs could not migrate towards the GC-exposed liver tissue, despite CXCR4 expression and the production of inflammatory cytokines from the liver cells. GC-treated MSCs were inefficient with respect to migration towards CXCL12, and this correlated with retracted cytoskeleton and motility. These dysfunctions were partly explained by decreases in the CXCL12/receptor axis. GC-associated decrease in MSCs in OLT recipients recovered post-transplant, despite poor migratory ability towards GC-exposed liver. In total, the study indicated that GC usage in transplant needs to be examined to determine if this could be reduced or avoided with adjuvant cell therapy.

Katherine Liu

Papers

Stem cell delivery of therapies for brain disorders

Non-canonical effects of anthrax toxins on haematopoiesis: implications for vaccine development.

Steroid-Mediated Decrease in Blood Mesenchymal Stem Cells in Liver Transplant could Impact Long-Term Recovery