Krisztián Németh

Bone marrow stromal cells attenuate sepsis via prostaglandin E 2 –dependent reprogramming of host macrophages to increase their interleukin-10 production

Sepsis causes over 200,000 deaths yearly in the US; better treatments are urgently needed. Administering bone marrow stromal cells (BMSCs—also known as mesenchymal stem cells) to mice before or shortly after inducing sepsis by cecal ligation and puncture reduced mortality and improved organ function. The beneficial effect of BMSCs was eliminated by macrophage depletion or pretreatment with antibodies specific for interleukin-10 (IL-10) or IL-10 receptor. Monocytes and/or macrophages from septic lungs made more IL-10 when prepared from mice treated with BMSCs versus untreated mice. Lipopolysaccharide (LPS)-stimulated macrophages produced more IL-10 when cultured with BMSCs, but this effect was eliminated if the BMSCs lacked the genes encoding Toll-like receptor 4, myeloid differentiation primary response gene-88, tumor necrosis factor (TNF) receptor-1a or cyclooxygenase-2. Our results suggest that BMSCs (activated by LPS or TNF-α) reprogram macrophages by releasing prostaglandin E2 that acts on the macrophages through the prostaglandin EP2 and EP4 receptors. Because BMSCs have been successfully given to humans and can easily be cultured and might be used without human leukocyte antigen matching, we suggest that cultured, banked human BMSCs may be effective in treating sepsis in high-risk patient groups.

Bone marrow stromal cells use TGF-β to suppress allergic responses in a mouse model of ragweed-induced asthma

Bone marrow stromal cells [BMSCs; also known as mesenchymal stem cells (MSCs)] effectively suppress inflammatory responses in acute graft-versus-host disease in humans and in a number of disease models in mice. Many of the studies concluded that BMSC-driven immunomodulation is mediated by the suppression of proinflammatory Th1 responses while rebalancing the Th1/Th2 ratio toward Th2. In this study, using a ragweed induced mouse asthma model, we studied if BMSCs could be beneficial in an allergic, Th2-dominant environment. When BMSCs were injected i.v. at the time of the antigen challenge, they protected the animals from the majority of asthma-specific pathological changes, including inhibition of eosinophil infiltration and excess mucus production in the lung, decreased levels of Th2 cytokines (IL-4, IL-5, and IL-13) in bronchial lavage, and lowered serum levels of Th2 immunoglobulins (IgG1 and IgE). To explore the mechanism of the effect we used BMSCs isolated from a variety of knockout mice, performed in vivo blocking of cytokines and studied the effect of asthmatic serum and bronchoalveolar lavage from ragweed challenged animals on the BMSCs in vitro. Our results suggest that IL-4 and/or IL-13 activate the STAT6 pathway in the BMSCs resulting in an increase of their TGF-β production, which seems to mediate the beneficial effect, either alone, or together with regulatory T cells, some of which might be recruited by the BMSCs. These data suggest that, in addition to focusing on graft-versus-host disease and autoimmune diseases, allergic conditions—specifically therapy resistant asthma—might also be a likely target of the recently discovered cellular therapy approach using BMSCs.

CD45‐Positive Blood Cells Give Rise to Uterine Epithelial Cells in Mice

The uterine endometrium is composed of epithelial and stromal cells, which undergo extensive degeneration and regeneration in every estrous cycle, and dramatic changes occur during pregnancy. The high turnover of cells requires a correspondingly high level of cell division by progenitor cells in the uterus, but the character and source of these cells remain obscure. In the present study, using a novel transgenic mouse, we showed that CD45‐positive hematopoietic progenitor cells colonize the uterine epithelium and that in pregnancy more than 80% of the epithelium can derive from these cells. Since we also found green fluorescent protein (GFP)‐positive uterine endothelial cells in long‐term GFP bone marrow‐transplanted mice, we conclude that circulating CD45+ cells play an important role in regenerating the uterine epithelium.

The combination of granulocyte colony-stimulating factor and stem cell factor significantly increases the number of bone marrow–derived endothelial cells in brains of mice following cerebral ischemia

Granulocyte colony-stimulating factor (G-CSF) induces proliferation of bone marrow-derived cells. G-CSF is neuroprotective after experimental brain injury, but the mechanisms involved remain unclear. Stem cell factor (SCF) is a cytokine important for the survival and differentiation of hematopoietic stem cells. Its receptor (c-kit or CD117) is present in some endothelial cells. We aimed to determine whether the combination of G-CSF/SCF induces angiogenesis in the central nervous system by promoting entry of endothelial precursors into the injured brain and causing them to proliferate there. We induced permanent middle cerebral artery occlusion in female mice that previously underwent sex-mismatched bone marrow transplantation from enhanced green fluorescent protein (EGFP)-expressing mice. G-CSF/SCF treatment reduced infarct volumes by more than 50% and resulted in a 1.5-fold increase in vessel formation in mice with stroke, a large percentage of which contain endothelial cells of bone marrow origin. Most cells entering the brain maintained their bone marrow identity and did not transdifferentiate into neural cells. G-CSF/SCF treatment also led to a 2-fold increase in the number of newborn cells in the ischemic hemisphere. These findings suggest that G-CSF/SCF treatment might help recovery through induction of bone marrow-derived angiogenesis, thus improving neuronal survival and functional outcome.

Placental expression profiling in preeclampsia: local overproduction of hemoglobin may drive pathological changes.

OBJECTIVE To create a library enriched in cDNAs from preeclamptic placentas to print onto microarrays for placental profiling of preeclampsia (PE) and high risk pregnancies. DESIGN Prospective study. SETTING University womens clinic and academic research laboratory. PATIENT(S) Ten patients with PE, 5 with PE and bilateral notching, 5 with bilateral notching without PE, and 15 normotensive patients were recruited. INTERVENTION(S) Placenta and placenta bed biopsies were collected after delivery. MAIN OUTCOME MEASURE(S) Subtracted libraries of PE transcripts were produced, and cDNAs from these libraries were used to make PE-specific cDNA arrays. Results were verified quantitatively using real-time polymerase chain reaction (PCR) and histologically using in situ hybridization and immunohistochemistry. RESULT(S) Thirty genes were significantly altered in at least one group comparison. Differences in two candidate genes were confirmed using quantitative real-time PCR. Hemoglobin alpha2 and gamma transcripts were significantly overexpressed in the PE placenta. Scattered cells in the placenta and placental blood vessels were shown to express genes encoding these hemoglobin chains. CONCLUSION(S) We demonstrate increased hemoglobin production in the PE placenta. The hemoglobin may be released into the placenta blood vessel lumen. Free heme and hemoglobin are potent toxins that cause endothelial damage and inflammation.

Bone marrow stromal cells inhibit mast cell function via a COX2‐dependent mechanism

Cite this as: J. M. Brown, K. Nemeth, N. M. Kushnir‐Sukhov, D. D. Metcalfe and E. Mezey, Clinical & Experimental Allergy, 2011 (41) 526–534.

Modulation of bone marrow stromal cell functions in infectious diseases by toll-like receptor ligands

Bone marrow-derived stromal cells (BMSCs, or as they are frequently referred to as mesenchymal stem cells) have been long known to support hematopoiesis and to regenerate bone, cartilage, and adipose tissue. In the last decade, however, a vast amount of data surfaced in the literature to suggest new roles for these cells including tissue regeneration and immunomodulation. A great number of review articles appeared that summarize these new data and focus on different aspects of the physiology of these cells. In this present short review, we will try to summarize the available data based on both mouse and human cells describing how the function of BMSCs might be affected by an infectious environment. These data strongly support the idea that different toll-like receptor ligands can lead to substantial changes in the function of BMSCs that affect their proliferation, apoptosis, migration, and their production and release of immunomodulatory factors.

Characterization and function of histamine receptors in human bone marrow stromal cells

There are several clinical trials worldwide using bone marrow stromal cells (BMSCs) as a cellular therapy to modulate immune responses in patients suffering from various inflammatory conditions. A deeper understanding of the molecular mechanisms involved in this modulatory effect could help us design better, more effective protocols to treat immune mediated diseases. In this study, we demonstrated that human BMSCs express H1, H2, and H4 histamine receptors and they respond to histamine stimulation with an increased interleukin 6 (IL‐6) production both in vitro and in vivo. Using different receptor antagonists, we pinpointed the importance of the H1 histamine receptor, while Western blot analysis and application of various mitogen‐activated protein kinase inhibitors highlighted the role of p38, extracellular signal‐regulated kinase, and c‐Jun N‐terminal kinase kinases in the observed effect. When BMSCs were pretreated with either histamine or degranulated human mast cells, they exhibited an enhanced IL‐6‐dependent antiapoptotic effect on neutrophil granulocytes. Based on these observations, it is likely that introduction of BMSCs into a histamine‐rich environment (such as any allergic setting) or pretreatment of these cells with synthetic histamine could have a significant modulatory effect on the therapeutic potential of BMSCs. STEM CELLS 2012; 30:222–231.

Unexpected roles for bone marrow stromal cells (or MSCs): a real promise for cellular, but not replacement, therapy

Adult and embryonic stem cells have drawn a lot of attention in the last decade as new tools in regenerative medicine. A variety of such cells have been discovered and put forward as candidates for use in cell replacement therapy. Investigators hope that some, if not all, of our organs can be replaced or restored to function; that new livers, kidneys, and brain cells can be produced. Many reviews have already been written about stem cells and their potential use in regenerating tissues. In this study, we would like to call attention to a different application of a special group of adult stem cells, the stromal cells in the bone marrow (also called mesenchymal stem cells or MSCs). These cells have been discovered to modulate immune function. They can easily be expanded in culture and surprisingly, they also seem not to be immunogenic. Thus, they can be removed from donors, expanded, stored in freezers, and used as allogeneic transplants in a variety of diseases in everyday medicine.

Bone marrow stromal cells as immunomodulators. A primer for dermatologists

Bone marrow stromal cells (BMSCs, also known as mesenchymal stem cells or MSCs) represent a unique cell population in the bone marrow with a long-known function to support hematopoiesis and replace skeletal tissues. The recent discovery that BMSCs also possess potent immunoregulatory features attracted a great deal of attention from stem cell biologists, immunologists and clinicians of different specialties worldwide. Initial clinical experience along with several animal models suggested that intravenously delivered BMSCs are able to regulate a wide variety of host immune cells and act in a way that is beneficial for the recipient in a variety of diseases. The role of the present review is to give a short introduction to the biology of BMSCs and to summarize our current understanding of how BMSCs modulate the immune system with special emphasis on available clinical data. Considering the audience of this journal we will also attempt to guide dermatologists in choosing the right skin conditions where BMSCs might be considered as a therapeutic alternative.