Multipotent mesenchymal stromal cells (MSC) have been widely explored for cell-based therapy of immune-mediated, inflammatory, and degenerative diseases, due to their immunosuppressive, immunomodulatory, and regenerative potentials. Preclinical studies and clinical trials have demonstrated promising therapeutic results although these have been somewhat limited. Aspects such as low in vivo MSC survival in inhospitable disease microenvironments, requirements for ex vivo cell overexpansion prior to infusions, intrinsic differences between MSC and different sources and donors, variability of culturing protocols, and potency assays to evaluate MSC products have been described as limitations in the field. In recent years, priming approaches to empower MSC have been investigated, thereby generating cellular products with improved potential for different clinical applications. Herein, we review the current priming approaches that aim to increase MSC therapeutic efficacy. Priming with cytokines and growth factors, hypoxia, pharmacological drugs, biomaterials, and different culture conditions, as well as other diverse molecules, are revised from current and future perspectives.

/pdf/priming-approaches-to-improve-the-efficacy-of-mesenchymal-4isyq540vw.pdf

Priming approaches to improve the efficacy of mesenchymal stromal cell-based therapies.

Mesenchymal stromal cells (MSCs), also known as mesenchymal stem cells, have been intensely investigated for clinical applications within the last decades. However, the majority of registered clinical trials applying MSC therapy for diverse human diseases have fallen short of expectations, despite the encouraging pre-clinical outcomes in varied animal disease models. This can be attributable to inconsistent criteria for MSCs identity across studies and their inherited heterogeneity. Nowadays, with the emergence of advanced biological techniques and substantial improvements in bio-engineered materials, strategies have been developed to overcome clinical challenges in MSC application. Here in this review, we will discuss the major challenges of MSC therapies in clinical application, the factors impacting the diversity of MSCs, the potential approaches that modify MSC products with the highest therapeutic potential, and finally the usage of MSCs for COVID-19 pandemic disease.

/pdf/challenges-and-advances-in-clinical-applications-of-1fp6n1lmv5.pdf

Challenges and advances in clinical applications of mesenchymal stromal cells.

Cancer stem cells (CSCs) are highly tumorigenic cell types that reside within specific areas of tumor microenvironment (TME), and are endowed with self-renewal and resistance properties. Here, we aimed to discuss mechanisms involved in hypoxia-derived CSC resistance and targeting for effective cancer therapy. Preferential localization within hypoxic niches would help CSCs develop adaptive mechanisms, mediated through the modification of responses to various stressors and, as a result, show a more aggressive behavior. Hypoxia, in fact, serves as a multi-tasking strategy to nurture CSCs with this adaptive capacity, complexing targeted therapies.

Hypoxia in solid tumors: a key promoter of cancer stem cell (CSC) resistance.

The development of protective agents against harmful radiations has been a subject of investigation for decades. However, effective (ideal) radioprotectors and radiomitigators remain an unsolved problem. Because ionizing radiation-induced cellular damage is primarily attributed to free radicals, radical scavengers are promising as potential radioprotectors. Early development of such agents focused on thiol synthetic compounds, e.g., amifostine (2-(3-aminopropylamino) ethylsulfanylphosphonic acid), approved as a radioprotector by the Food and Drug Administration (FDA, USA) but for limited clinical indications and not for nonclinical uses. To date, no new chemical entity has been approved by the FDA as a radiation countermeasure for acute radiation syndrome (ARS). All FDA-approved radiation countermeasures (filgrastim, a recombinant DNA form of the naturally occurring granulocyte colony-stimulating factor, G-CSF; pegfilgrastim, a PEGylated form of the recombinant human G-CSF; sargramostim, a recombinant granulocyte macrophage colony-stimulating factor, GM-CSF) are classified as radiomitigators. No radioprotector that can be administered prior to exposure has been approved for ARS. This differentiates radioprotectors (reduce direct damage caused by radiation) and radiomitigators (minimize toxicity even after radiation has been delivered). Molecules under development with the aim of reaching clinical practice and other nonclinical applications are discussed. Assays to evaluate the biological effects of ionizing radiations are also analyzed.

https://www.mdpi.com/2227-9059/8/11/461/pdf

Radioprotection and Radiomitigation: From the Bench to Clinical Practice.

Mesenchymal stem cells (MSCs) are broadly used in cell-based regenerative medicine because of their self-renewal and multilineage potencies in vitro and in vivo To ensure sufficient amounts of MSCs for therapeutic purposes, cells are generally cultured in vitro for long-term expansion or specific terminal differentiation until cell transplantation Although physiologically up-regulated reactive oxygen species (ROS) production is essential for maintenance of stem cell activities, abnormally high levels of ROS can harm MSCs both in vitro and in vivo Overall, additional elucidation of the mechanisms by which physiological and pathological ROS are generated is necessary to better direct MSC fates and improve their therapeutic effects by controlling external ROS levels In this review, we focus on the currently revealed ROS generation mechanisms and the regulatory routes for controlling their rates of proliferation, survival, senescence, apoptosis, and differentiation A promising strategy in future regenerative medicine involves regulating ROS generation via various means to augment the therapeutic efficacy of MSCs, thus improving the prognosis of patients with terminal diseases

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/jcmm.13835

Regulation of the mitochondrial reactive oxygen species: Strategies to control mesenchymal stem cell fates ex vivo and in vivo.

Background/Aims: Radiation therapy is an important treatment for thoracic cancer; however, side effects accompanied with radiotherapy lead to limited tumor control and a decline in patient quality of life. Among these side effects, radiation-induced lung injury (RILI) is the most serious and common. Hence, an effective remedy for RILI is needed. Mesenchymal stromal cells (MSCs) are multipotent adult stem cells that have been demonstrated to be an effective treatment in some disease caused by tissue damage. However, unlike other injuries, RILI received limited therapeutic effects from implanted MSCs due to local hypoxia and extensive reactive oxygen species (ROS) in irradiated lungs. Since the poor survival of MSCs is primarily due to hypoxia and ROS generation, we hypothesize that persistent and adaptive hypoxia treatment induces enhanced resistance to hypoxic stress in implanted MSC. The aim of this study is to investigate whether persistent and adaptive hypoxia treatment of bmMSCs prior to their transplantation in injured mice enhanced survival and improved curative effects in RILI. Methods: Primary bmMSCs were obtained from the marrow of six-week-old male C57BL6/J mice and were cultured either under normoxic conditions (21% O 2 ) or hypoxic conditions (2.5% O 2 ). Mice were injected with normoxia/hypoxia MSCs after thoracic irradiation (20 Gy). The therapeutic effects of MSCs on RILI were assessed by pathological examinations that included HE meanwhile, inflammatory factors were measured using an ELISA. The morphology of MSCs in vitro was recorded using a microscope and identified by flow cytometry, cell viability was measured using the CCK-8 assay, the potential for proliferation was detected by the EdU assay, and ROS levels were measured using a ROS fluorogenic probe. In addition, HIF-1α and several survival pathway proteins (Akt, p-Akt, Caspase-3) were also detected by western blotting. Results: Implanted MSCs alleviated both early radiation-induced pneumonia and late pulmonary fibrosis. However, hypoxia MSCs displayed a more pronounced therapeutic effect compared to normoxia MSCs. Compared to normoxia MSCs, the hypoxia MSCs demonstrated greater cell viability, an enhanced proliferation potential, decreased ROS levels and increased resistance to hypoxia and ROS stress. In addition, hypoxia MSCs achieved higher activation levels of HIF-1α and Akt, and HIF-1α played a critical role in the development of resistance. Conclusion: Hypoxia enhances the therapeutic effect of mesenchymal stromal cells on radiation-induced lung injury by promoting MSC proliferation and improving their antioxidant ability, mediated by HIF-1α.

/pdf/hypoxia-induced-mesenchymal-stromal-cells-exhibit-an-fbzti4v6hd.pdf

Hypoxia-Induced Mesenchymal Stromal Cells Exhibit an Enhanced Therapeutic Effect on Radiation-Induced Lung Injury in Mice due to an Increased Proliferation Potential and Enhanced Antioxidant Ability.

The invention discloses a crew maritime intra-cabin positioning, vital sign monitoring and searching-rescuing method based on a crew maritime intra-cabin positioning, vital sign monitoring and searching-rescuing system. The system comprises a command center server, an electronic fence transmitter, a crew vital sign real-time monitor, a crew real-time positioner, a shipboard personnel positioning processor and an overboard personnel positioner. According to the method, the vital sign real-time monitor for a single crew member, the shipboard and overboard personnel real-time positioners as well as wounded personnel vital sign and positioning data transmission are researched on the basis of such modern information technologies as AIS (automatic identification system), UWB (ultra-wide band), compass navigation positioning and the like, so that the automation of maritime wounded personnel vital sign monitoring, the electronization of information storage, the networking of information transmission and the visualization wounded personnel rescuing are achieved.

Crew maritime intra-cabin positioning, vital sign monitoring and searching-rescuing method

BACKGROUND Carbon ion radiotherapy has been shown to be more effective in cancer radiotherapy than photon irradiation. Influence of carbon ion radiation on cancer microenvironment is very important for the outcomes of radiotherapy. Tumor-infiltrating dendritic cells (DCs) play critical roles in cancer antigen processing and antitumor immunity. However, there is scant literature covering the effects of carbon ion radiation on DCs. In this study, we aimed to uncover the impact of carbon ion irradiation on bone marrow derived DCs. MATERIAL AND METHODS Bone marrow cells were co-cultured with GM-CSF and IL-4 for seven days, and the population of DCs was confirmed with flow cytometry. We used an Annexin V and PI staining method to detect cell apoptosis. Endocytosis assay of DCs was determined by using a flow cytometry method. DCs migration capacity was tested by a Transwell method. We also used ELISA assay and western blotting assay to examine the cytokines and protein expression, respectively. RESULTS Our data showed that carbon ion radiation induced apoptosis in both immature and mature DCs. After irradiation, the endocytosis and migration capacity of DCs was also impaired. Interestingly, carbon irradiation triggered a burst of IFN-g and IL-12 in LPS or CpG treated DCs, which provide novel insights into the combination of immunotherapy and carbon ion radiotherapy. Finally, we found that carbon ion irradiation induced apoptosis and migration suppression was p38 dependent. CONCLUSIONS Our present study demonstrated that carbon ion irradiation induced apoptosis in DCs, and impaired DCs function mainly through the p38 signaling pathway. Carbon ion irradiation also triggered anti-tumor cytokines secretion. This work provides novel information of carbon ion radiotherapy in DCs, and also provides new insights on the combination of immune adjuvant and carbon ion radiotherapy.

/pdf/effects-of-12c6-heavy-ion-radiation-on-dendritic-cells-1lmdx73tkn.pdf

Effects of 12C6+ Heavy Ion Radiation on Dendritic Cells Function.

Radiation-induced lung injury (RILI) is a common and severe side effect of thoracic radiotherapy, which compromises patients' quality of life. Recent studies revealed that early vascular injury, especially microvascular damage, played a central role in the development of RILI. For this reason, early vascular protection is essential for RILI therapy. The ATP-sensitive K+ (KATP) channel is an ATP-dependent K+ channel with multiple subunits. The protective role of the KATP channel in vascular injury has been demonstrated in some published studies. In this work, we investigated the effect of KATP channel on RILI. Our findings confirmed that the KATP channel blocker glibenclamide, rather than the KATP channel opener pinacidil, remitted RILI, and in particular, provided protection against radiation-induced vascular injury. Cytology experiments verified that glibenclamide enhanced cell viability, increased the potential of proliferation after irradiation and attenuated radiation-induced apoptosis. Involved mechanisms included increased Ca2+ influx and PKC activation, which were induced by glibenclamide pretreatment. In conclusion, the KATP channel blocker glibenclamide remitted RILI and inhibited the radiation-induced apoptosis of vascular endothelial cells by increased Ca2+ influx and subsequent PKC activation.

KATP Channel Blocker Glibenclamide Prevents Radiation-Induced Lung Injury and Inhibits Radiation-Induced Apoptosis of Vascular Endothelial Cells by Increased Ca2+ Influx and Subsequent PKC Activation.

Bin Liu

Papers

Hypoxia-Induced Mesenchymal Stromal Cells Exhibit an Enhanced Therapeutic Effect on Radiation-Induced Lung Injury in Mice due to an Increased Proliferation Potential and Enhanced Antioxidant Ability.

Crew maritime intra-cabin positioning, vital sign monitoring and searching-rescuing method

Effects of 12C6+ Heavy Ion Radiation on Dendritic Cells Function.

KATP Channel Blocker Glibenclamide Prevents Radiation-Induced Lung Injury and Inhibits Radiation-Induced Apoptosis of Vascular Endothelial Cells by Increased Ca2+ Influx and Subsequent PKC Activation.