Beneficial Effects Of Mesenchymal Stromal Cells Research Articles

Key Role of Mesenchymal Stromal Cell Interaction with Macrophages in Promoting Repair of Lung Injury.

Lung macrophages (Mφs) are essential for pulmonary innate immunity and host defense due to their dynamic polarization and phenotype shifts. Mesenchymal stromal cells (MSCs) have secretory, immunomodulatory, and tissue-reparative properties and have shown promise in acute and chronic inflammatory lung diseases and in COVID-19. Many beneficial effects of MSCs are mediated through their interaction with resident alveolar and pulmonary interstitial Mφs. Bidirectional MSC-Mφ communication is achieved through direct contact, soluble factor secretion/activation, and organelle transfer. The lung microenvironment facilitates MSC secretion of factors that result in Mφ polarization towards an immunosuppressive M2-like phenotype for the restoration of tissue homeostasis. M2-like Mφ in turn can affect the MSC immune regulatory function in MSC engraftment and tissue reparatory effects. This review article highlights the mechanisms of crosstalk between MSCs and Mφs and the potential role of their interaction in lung repair in inflammatory lung diseases.

Mesenchymal Stromal Cell Secretome for the Treatment of Immune-Mediated Inflammatory Diseases: Latest Trends in Isolation, Content Optimization and Delivery Avenues.

Considering the high prevalence and the complex pharmacological management of immune-mediated inflammatory diseases (IMIDs), the search for new therapeutic approaches for their treatment is vital. Although the immunomodulatory and anti-inflammatory effects of mesenchymal stromal cells (MSCs) have been extensively studied as a potential therapy in this field, direct MSC implantation presents some limitations that could slow down the clinical translation. Since the beneficial effects of MSCs have been mainly attributed to their ability to secrete a plethora of bioactive factors, their secretome has been proposed as a new and promising pathway for the treatment of IMIDs. Formed from soluble factors and extracellular vesicles (EVs), the MSC-derived secretome has been proven to elicit immunomodulatory effects that control the inflammatory processes that occur in IMIDs. This article aims to review the available knowledge on the MSC secretome, evaluating the advances in this field in terms of its composition, production and application, as well as analyzing the pending challenges in the field. Moreover, the latest research involving secretome administration in IMIDs is discussed to provide an updated state-of-the-art for this field. Finally, novel secretome delivery alternatives are reviewed, paying special attention to hydrogel encapsulation as one of the most convenient and promising strategies.

Therapeutic Implications of Mesenchymal Stromal Cells and Their Extracellular Vesicles in Autoimmune Diseases: From Biology to Clinical Applications.

Mesenchymal stromal cells (MSCs) are perivascular multipotent stem cells originally identified in the bone marrow (BM) stroma and subsequently in virtually all vascularized tissues. Because of their ability to differentiate into various mesodermal lineages, their trophic properties, homing capacity, and immunomodulatory functions, MSCs have emerged as attractive candidates in tissue repair and treatment of autoimmune disorders. Accumulating evidence suggests that the beneficial effects of MSCs may be primarily mediated via a number of paracrine-acting soluble factors and extracellular vesicles (EVs). EVs are membrane-coated vesicles that are increasingly being acknowledged as playing a key role in intercellular communication via their capacity to carry and deliver their cargo, consisting of proteins, nucleic acids, and lipids to recipient cells. MSC-EVs recapitulate the functions of the cells they originate, including immunoregulatory effects but do not seem to be associated with the limitations and concerns of cell-based therapies, thereby emerging as an appealing alternative therapeutic option in immune-mediated disorders. In the present review, the biology of MSCs will be outlined and an overview of their immunomodulatory functions will be provided. In addition, current knowledge on the features of MSC-EVs and their immunoregulatory potential will be summarized. Finally, therapeutic applications of MSCs and MSC-EVs in autoimmune disorders will be discussed.

Mesenchymal stromal cells: what have we learned so far about their therapeutic potential and mechanisms of action?

Mesenchymal stromal cells (MSCs) have been found to be safe and effective in a wide range of animal models of human disease. MSCs have been tested in thousands of clinical trials, but results show that while these cells appear to be safe, they tend to lack efficacy. This has raised questions about whether animal models are useful for predicting efficacy in patients. However, a problem with animal studies is that there is a lack of standardisation in the models and MSC therapy regimes used; there appears to be publication bias towards studies reporting positive outcomes; and the reproducibility of results from animal experiments tends not to be confirmed prior to clinical translation. A further problem is that while some progress has been made towards investigating the mechanisms of action (MoA) of MSCs, we still fail to understand how they work. To make progress, it is important to ensure that prior to clinical translation, the beneficial effects of MSCs in animal studies are real and can be repeated by independent research groups. We also need to understand the MoA of MSCs to assess whether their effects are likely to be beneficial across different species. In this review, we give an overview of the current clinical picture of MSC therapies and discuss what we have learned from animal studies. We also give a comprehensive update of what we know about the MoA of MSCs, particularly in relation to their role in immunomodulation.

Mesenchymal Stromal Cells Improve Survival During Sepsis in the Absence of Heme Oxygenase-1: The Importance of Neutrophils

The use of mesenchymal stromal cells (MSCs) for treatment of bacterial infections, including systemic processes like sepsis, is an evolving field of investigation. This study was designed to investigate the potential use of MSCs, harvested from compact bone, and their interactions with the innate immune system, during polymicrobial sepsis induced by cecal ligation and puncture (CLP). We also wanted to elucidate the role of endogenous heme oxygenase (HO)-1 in MSCs during a systemic bacterial infection. MSCs harvested from the bones of HO-1 deficient (-/-) and wild-type (+/+) mice improved the survival of HO-1(-/-) and HO-1(+/+) recipient mice when administered after the onset of polymicrobial sepsis induced by CLP, compared with the administration of fibroblast control cells. The MSCs, originating from compact bone in mice, enhanced the ability of neutrophils to phagocytize bacteria in vitro and in vivo and to promote bacterial clearance in the peritoneum and blood after CLP. Moreover, after depleting neutrophils in recipient mice, the beneficial effects of MSCs were entirely lost, demonstrating the importance of neutrophils for this MSC response. MSCs also decreased multiple organ injury in susceptible HO-1(-/-) mice, when administered after the onset of sepsis. Taken together, these data demonstrate that the beneficial effects of treatment with MSCs after the onset of polymicrobial sepsis is not dependent on endogenous HO-1 expression, and that neutrophils are crucial for this therapeutic response.

Immune Effects of Mesenchymal Stromal Cells in Experimental Stroke

Preclinical trials confirmed the potential of mesenchymal stromal cells (MSCs) to improve functional recovery after experimental stroke. Beneficial effects of MSCs are often attributed to their immunosuppressive/immunomodulatory functions. Surprisingly, the influence of MSCs on the immune system after stroke is poorly understood, but requires special consideration because cerebral ischemia is associated with stroke-induced immunodepression that predisposes to bacterial infections with increased mortality. In this study, we intravenously transplanted syngeneic murine bone marrow-derived MSCs (mMSCs) into C57BL/6 mice at 6 hours after transient middle cerebral artery occlusion (MCAo; 60 minutes) to investigate the impact of MSCs on stroke-induced immunodepression. Transplantation of syngeneic splenocytes or phosphate-buffered saline (PBS) served as controls. An immune status was determined by flow cytometry on days 3 and 14 after MCAo, which did not reveal any negative effects of cell transplantation on stroke-induced immunodepression. Although our mMSCs were found to exert immunosuppressive effects in vitro, stroke-mediated immune cell dysfunction was not altered by mMSCs in ex-vivo stimulation assays with lipopolysaccharide or concanavalin A. Moreover, systemic inflammatory cytokine levels (interleukin-6, tumor necrosis factorα, interferonγ, monocyte chemoattractant protein-1) remained unchanged in the sera of mice after cerebral ischemia and cell transplantation. These results reduce safety concerns about MSC administration in ongoing clinical stroke trials.

Mesenchymal stromal cells in renal ischemia/reperfusion injury

Ischemia/reperfusion (I/R) injury is an inevitable consequence of organ transplantation and a major determinant of patient and graft survival in kidney transplantation. Renal I/R injury can lead to fibrosis and graft failure. Although the exact sequence of events in the pathophysiology of I/R injury remains unknown, the role of inflammation has become increasingly clear. In this perspective, mesenchymal stromal cells (MSCs) are under extensive investigation as potential therapy for I/R injury, since MSCs are able to exert immune regulatory and reparative effects. Various preclinical studies indicate the beneficial effects of MSCs in ameliorating renal injury and accelerating tissue repair. These versatile cells have been shown to migrate to sites of injury and to enhance repair by paracrine mechanisms instead of by differentiating and replacing the injured cells. The first phase I studies of MSCs in human renal I/R injury and kidney transplantation have been started, and results are awaited soon. In this review, preliminary results and opportunities of MSCs in human renal I/R injury are summarized. We might be heading towards a cell-based paradigm shift in the treatment of renal I/R injury.