Autoimmune diseases (ADs), such as Graves' disease (GD), Hashimoto's thyroiditis (HT), psoriasis, systemic lupus erythematosus (SLE), and type 1 diabetes (T1D), involve complex immune and inflammatory responses. This study employed Mendelian randomization (MR) analysis using genome-wide association study (GWAS) data to examine the causal relationships among 91 circulating inflammatory proteins, 41 cytokines, 211 gut microbiota, and 731 immune cell traits in relation to ADs. Additionally, we integrated mediation and bioinformatics analyses, including protein-protein interaction (PPI) networks, Gene Ontology (GO) enrichment, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Subnetwork discovery and key protein identification were performed using the Molecular Complex Detection (MCODE) plugin, alongside colocalization analysis and drug target exploration to identify potential mechanisms. MR analysis identified significant causal relationships between various circulating inflammatory proteins, cytokines, gut microbiota species, immune cells, and ADs, with certain relationships retaining significance after false discovery rate (FDR) correction. Mediation analysis demonstrated that inflammatory proteins mediate pathogenic pathways linking immune cells to psoriasis and gut microbiota to Hashimoto's thyroiditis. PPI and bioinformatics analyses highlighted 22 key proteins involved in ADs, while subnetwork analysis identified 15 central proteins. Fms-related tyrosine kinase 3 ligand (FLT3LG) exhibited strong colocalization evidence. Molecular docking confirmed several proteins as viable drug targets. This comprehensive multi-omics study advances our understanding of ADs, identifies novel therapeutic targets, and offers valuable insights for developing new treatment strategies.

Systemic sclerosis (SSc) is a chronic autoimmune disease that includes fibrosis, diffuse vasculopathy, inflammation, and autoimmunity. Autologous hematopoietic stem cell transplantation (auto-HSCT) is considered for patients with severe and progressive SSc. In recent decades, knowledge about patient management and clinical outcomes after auto-HSCT has significantly improved. Mechanistic studies have contributed to increasing the comprehension of how profound and long-lasting are the modifications to the immune system induced by transplantation. This review revisits the immune monitoring studies after auto-HSCT for SSc patients and how they relate to clinical outcomes. This understanding is essential to further improve clinical applications of auto-HSCT and enhance patient outcomes.

Mesenchymal stem cells are undifferentiated cells able to acquire different phenotypes under specific stimuli. In vitro manipulation of these cells is focused on understanding stem cell behavior, proliferation and pluripotency. Latest advances in the field of stem cells concern epigenetics and its role in maintaining self-renewal and differentiation capabilities. Chemical and physical stimuli can modulate cell commitment, acting on gene expression of Oct-4, Sox-2 and Nanog, the main stemness markers, and tissue-lineage specific genes. This activation or repression is related to the activity of chromatin-remodeling factors and epigenetic regulators, new targets of many cell therapies. The aim of this review is to afford a view of the current state of in vitro and in vivo stem cell applications, highlighting the strategies used to influence stem cell commitment for current and future cell therapies. Identifying the molecular mechanisms controlling stem cell fate could open up novel strategies for tissue repairing processes and other clinical applications.

Rational pathway design is the invention of an optimally efficient route from one state (e.g. chemical structure, state of differentiation, physiological state) to another, based on knowledge of biological processes: it contrasts with the use of natural pathways that have evolved by natural selection. Synthetic biology is a hybrid discipline of biology and engineering that offers a means for rationally designed pathways to be realized in living cells. Several areas of regenerative medicine could benefit from rational pathway design, including derivation of patient-specific stem cells, directed differentiation of stem cells, replicating physiological function in an alternative cell type, construction of custom interface tissues and building fail-safe systems into transplanted tissues. Synthetic biological approaches offer the potential for construction of these, for example controllable ex vivo stem cell niches, genetic networks for direct transdifferentiation from adult fibroblast to restricted stem cell without going via induced pluripotent stem cells, signalling pathways for realizing physiological regulation in alternative cell types, morphological modules for producing self-constructing novel 'tissues' and 'kill-switches' for therapeutically applied stem cells. Given the potential of this approach, a closer convergence of the regenerative medicine and synthetic biology research fields seems timely.

To investigate the efficacy and safety of targeted delivery of autologous bone marrow mononuclear cells (BMMCs), which are highly enriched with mesenchymal stem cells (BMMSCs), via medial circumflex femoral artery in the treatment of osteonecrosis of the femoral head (ONFH).

62 patients (78 hips) with ONFH were recruited in this study. All of these patients were treated with BMMCs perfusion via medial circumflex femoral artery. The concentrated BMMCs (30-60ml) were gained from autologous bone marrow (100-200ml) harvested from anterior iliac crest and then were intra-arterially perfused into the femoral head. Ficat stage was used to classify the radiological stage of ONFH. Harris hip score was used to evaluate the clinical symptoms of osteonecrosis. Ficat stage and Harris hip scores were assessed at onset of treatment at 6, 12, 24, 36, 48 and 60months after the initial treatment. Total hip arthroplasty (THA) was also assessed as an endpoint at each follow-up.

A follow-up on the patient was done at the end of five years, and 92.31% (72 of 78) of hips achieved a satisfactory clinical result while only 6 hips (7.69%) progressed to clinical failure and required THA. Radiological progression was noted in 34 of 78 hips (43.59%); the overall rate of collapse was 38.24% (26 of 68 hips) in stage-I and stage-II hip combinations and 12.5% (2 of 16) in stage-I hips and 46.15% (24 of 52) in stage-II hips. The mean time of conversion to THA was 3years (1 to 5years) and the average time to collapse were 3.5years (1-5years). The mean Harris hip score increased from 59 points at baseline to 75 points at 12months, 82 points at 24months, 81 points at 36months, 79 points at 48months and 74 points at 60months. Five years after the treatment, 3 of 10 hips (30%) in stage-III had deteriorated to clinical failure whereas only 3 of 68 hips (4.41%) in stage-I and II combination had progressed to clinical failure (p<0.05). Kaplan-Meier survival analysis showed a significant difference in the time to failure between the pre-collapse hips (Ficat stage-I and II) and the post-collapse hips (Ficat stage-III) at five years follow-up (Log-rank test; p<0.01). No complication was found in any patients.

Autologous BMMSC perfusion via the medial circumflex femoral artery can relieve symptoms, improve hip function and delay the progression of ONFH. The clinical outcome is better when it is applied prior to the collapse. This work demonstrates that autologous BMMSC perfusion via the medial circumflex femoral artery is a safe, effective and minimally invasive treatment strategy for early-stage ONFH.

Hematopoietic stem-cell transplant (HSCT) is associated with many risk factors for life-threatening complications. Post-transplant critical illness often requires admission to the pediatric intensive care unit (PICU).

A retrospective analysis was made on the risk factors associated with PICU admission and mortality of all HSCT patients at Helen DeVos Children's Hospital from October 1998 to November 2008.

One hundred and twenty-four patients underwent HSCT, with 19 (15.3%) requiring 29 PICU admissions. Fifty patients received autologous, 38 matched sibling, and 36 matched un-related donor HSCT, with 10%, 13% and 25% of these patients requiring PICU admission, respectively (P=0.01). Among the HSCT patients, those who were admitted to the PICU were more likely to have renal involvement by either malignancy requiring nephrectomy or a post transplant complication increasing the likelihood of decreased renal function (21.1% vs. 4.8%, P=0.03). PICU admissions were also more likely to receive pre-transplant total body irradiation (52.6% vs. 27.6%, P=0.03). Among 29 patients with PICU admission, 3 died on day 1 after admission, and 5 within 30 days (a mortality rate of 17%). Thirty days after PICU admission, non-survivors had a higher incidence of respiratory failure and septic shock on admission compared with survivors (80% vs. 16.7%, P=0.01 and 80% vs. 4.2%, respectively, P=0.001). Two survivors with chronic renal failure underwent renal transplantation successfully.

Total body irradiation and renal involvement are associated with higher risk for PICU admissions after HSCT in pediatric patients, while septic shock upon admission and post-admission respiratory failure are associated with mortality.

Myeloablative (MyA) bone marrow transplantation (BMT) results in robust engraftment of BMT-derived cells in the central nervous system (CNS) and is neuroprotective in diverse experimental models of neurodegenerative diseases of the brain and retina. However, MyA irradiation is associated with significant morbidity and mortality and does not represent a viable therapeutic option for the elderly. Non-myeloablative (NMyA) BMT is less toxic, but it is not known if the therapeutic efficacy observed with MyA BMT is preserved. As a first step to address this important gap in knowledge, we evaluated and compared engraftment characteristics of BMT-derived monocytes/microglia using several clinically relevant NMyA pretransplant conditioning regimens in C57BL/6 mice. These included chemotherapy (fludarabine and cyclophosphamide) with or without 2 Gy irradiation, and 5.5 Gy irradiation alone. Each regimen was followed by transplantation of whole bone marrow from green fluorescent protein-expressing wild type (wt) mice. While stable hematopoietic engraftment occurred, to varying degrees, in all NMyA regimens, only 5.5 Gy irradiation resulted in significant engraftment of BMT-derived cells in the brain, where these cells were exclusively localized to perivascular, leptomeningeal, and related anatomic regions. Engraftment in retina under 5.5 Gy NMyA conditions was significantly reduced compared to MyA, but robust engraftment was identified in the optic nerve. Advancing the therapeutic applications of BMT to neurodegenerative diseases will require identification of the barrier mechanisms that MyA, but not NMyA, BMT is able to overcome.

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by T cell-mediated destruction of pancreatic β cells, resulting in insulin deficiency and hyperglycaemia. Recent studies have described that apoptosis impairment during central and peripheral tolerance is involved in T1D pathogenesis. In this study, the apoptosis-related gene expression in T1D patients was evaluated before and after treatment with high-dose immunosuppression followed by autologous haematopoietic stem cell transplantation (HDI-AHSCT). We also correlated gene expression results with clinical response to HDI-AHSCT. We observed a decreased expression of bad, bax and fasL pro-apoptotic genes and an increased expression of a1, bcl-x(L) and cIAP-2 anti-apoptotic genes in patients' peripheral blood mononuclear cells (PBMCs) compared to controls. After HDI-AHSCT, we found an up-regulation of fas and fasL and a down-regulation of anti-apoptotic bcl-x(L) genes expression in post-HDI-AHSCT periods compared to pre-transplantation. Additionally, the levels of bad, bax, bok, fasL, bcl-x(L) and cIAP-1 genes expression were found similar to controls 2 years after HDI-AHSCT. Furthermore, over-expression of pro-apoptotic noxa at 540 days post-HDI-AHSCT correlated positively with insulin-free patients and conversely with glutamic acid decarboxylase autoantibodies (GAD65) autoantibody levels. Taken together, the results suggest that apoptosis-related genes deregulation in patients' PBMCs might be involved in breakdown of immune tolerance and consequently contribute to T1D pathogenesis. Furthermore, HDI-AHSCT modulated the expression of some apoptotic genes towards the levels similar to controls. Possibly, the expression of these apoptotic molecules could be applied as biomarkers of clinical remission of T1D patients treated with HDI-AHSCT therapy.

The clinical care of patients with type 1 diabetes (T1D) has greatly improved over the past few decades; however, it remains impossible to completely normalize blood sugar utilizing currently available tools. Research is underway with a goal to improve the care and, ultimately, to cure T1D by preserving beta cells. This review will outline the progress that has been made in trials aimed at preserving insulin secretion in T1D by modifying the immune assault on the pancreatic beta cell. Although not yet ready for clinical use, successful trials have been conducted in new-onset T1D that demonstrated utility of three experimental agents with disparate modes of action (anti-T cell, anti-B cell, and costimulation blockade) to preserve insulin secretion. In contrast, prevention studies have so far failed to produce positive results but have shown that such studies are feasible and have identified new promising agents for study.

In this study, we investigated the feasibility and safety of intravenous transplantation of allogeneic bone marrow mesenchymal stem cells (MSCs) for femoral head repair, and observed the migration and distribution of MSCs in hosts. MSCs were labeled with green fluorescent protein (GFP) in vitro and injected into nude mice via vena caudalis, and the distribution of MSCs was dynamically monitored at 0, 6, 24, 48, 72 and 96 h after transplantation. Two weeks after the establishment of a rabbit model of femoral head necrosis, GFP labeled MSCs were injected into these rabbits via ear vein, immunological rejection and graft versus host disease were observed and necrotic and normal femoral heads, bone marrows, lungs, and livers were harvested at 2, 4 and 6 w after transplantation. The sections of these tissues were observed under fluorescent microscope. More than 70 % MSCs were successfully labeled with GFP at 72 h after labeling. MSCs were uniformly distributed in multiple organs and tissues including brain, lungs, heart, kidneys, intestine and bilateral hip joints of nude mice. In rabbits, at 6 w after intravenous transplantation, GFP labeled MSCs were noted in the lungs, liver, bone marrow and normal and necrotic femoral heads of rabbits, and the number of MSCs in bone marrow was higher than that in the, femoral head, liver and lungs. Furthermore, the number of MSCs peaked at 6 w after transplantation. Moreover, no immunological rejection and graft versus host disease were found after transplantation in rabbits. Our results revealed intravenously implanted MSCs could migrate into the femoral head of hosts, and especially migrate directionally and survive in the necrotic femoral heads. Thus, it is feasible and safe to treat femoral head necrosis by intravenous transplantation of allogeneic MSCs.