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Journal: Stem cells translational medicine

250

Dentin-pulp complex regeneration is a promising alternative treatment for the irreversible pulpitis caused by tooth trauma or dental caries. This process mainly relies on the recruitment of endogenous or the transplanted dental pulp stem cells (DPSCs) to guide dentin-pulp tissue formation. Platelet-derived growth factor (PDGF), a well-known potent mitogenic, angiogenic, and chemoattractive agent, has been widely used in tissue regeneration. However, the mechanisms underlying the therapeutic effects of PDGF on dentin-pulp complex regeneration are still unclear. In this study, we tested the effect of PDGF-BB on dentin-pulp tissue regeneration by establishing PDGF-BB gene-modified human dental pulp stem cells (hDPSCs) using a lentivirus. Our results showed that PDGF-BB can significantly enhance hDPSC proliferation and odontoblastic differentiation. Furthermore, PDGF-BB and vascular endothelial growth factor (VEGF) secreted by hDPSCs enhanced angiogenesis. The chemoattractive effect of PDGF-BB on hDPSCs was also confirmed using a Transwell chemotactic migration model. We further determined that PDGF-BB facilitates hDPSCs migration via the activation of the phosphatidylinositol 3 kinase (PI3K)/Akt signaling pathway. In vivo, CM-DiI-labeled hDPSCs were injected subcutaneously into mice, and our results showed that more labeled cells were recruited to the sites implanted with calcium phosphate cement scaffolds containing PDGF-BB gene-modified hDPSCs. Finally, the tissue-engineered complexes were implanted subcutaneously in mice for 12 weeks, the Lenti-PDGF group generated more dentin-like mineralized tissue which showed positive staining for the DSPP protein, similar to tooth dentin tissue, and was surrounded by highly vascularized dental pulp-like connective tissue. Taken together, our data demonstrated that the PDGF-BB possesses a powerful function in prompting stem cell-based dentin-pulp tissue regeneration. Stem Cells Translational Medicine 2017.

Concepts: Angiogenesis, Growth factor, Vascular endothelial growth factor, Cellular differentiation, Teeth, Dental caries, Dentin, Platelet-derived growth factor

180

Cerebral palsy (CP) is a condition affecting young children that causes lifelong disabilities. Umbilical cord blood cells improve motor function in experimental systems via paracrine signaling. After demonstrating safety, we conducted a Phase II trial of autologous cord blood (ACB) infusion in children with CP to test whether ACB could improve function (ClinicalTrials.gov, NCT01147653; IND 14360). In this double-blind, placebo-controlled, crossover study of a single intravenous infusion of 1-5 × 10(7) total nucleated cells per kilogram of ACB, children ages 1 to 6 years with CP were randomly assigned to receive ACB or placebo at baseline, followed by the alternate infusion 1 year later. Motor function and magnetic resonance imaging brain connectivity studies were performed at baseline, 1, and 2 years post-treatment. The primary endpoint was change in motor function 1 year after baseline infusion. Additional analyses were performed at 2 years. Sixty-three children (median age 2.1 years) were randomized to treatment (n = 32) or placebo (n = 31) at baseline. Although there was no difference in mean change in Gross Motor Function Measure-66 (GMFM-66) scores at 1 year between placebo and treated groups, a dosing effect was identified. In an analysis 1 year post-ACB treatment, those who received doses ≥2 × 10(7) /kg demonstrated significantly greater increases in GMFM-66 scores above those predicted by age and severity, as well as in Peabody Developmental Motor Scales-2 Gross Motor Quotient scores and normalized brain connectivity. Results of this study suggest that appropriately dosed ACB infusion improves brain connectivity and gross motor function in young children with CP. Stem Cells Translational Medicine 2017.

Concepts: Cell nucleus, Clinical trial, Stem cell, Magnetic resonance imaging, Umbilical cord, Cord blood, Wharton's jelly, Cord blood bank

178

Diabetes is a major global health issue and the number of individuals with type 1 diabetes (T1D) and type 2 diabetes (T2D) increases annually across multiple populations. Research to develop a cure must overcome multiple immune dysfunctions and the shortage of pancreatic islet β cells, but these challenges have proven intractable despite intensive research effort more than the past decades. Stem Cell Educator (SCE) therapy-which uses only autologous blood immune cells that are externally exposed to cord blood stem cells adhering to the SCE device, has previously been proven safe and effective in Chinese and Spanish subjects for the improvement of T1D, T2D, and other autoimmune diseases. Here, 4-year follow-up studies demonstrated the long-term safety and clinical efficacy of SCE therapy for the treatment of T1D and T2D. Mechanistic studies found that the nature of platelets was modulated in diabetic subjects after receiving SCE therapy. Platelets and their released mitochondria display immune tolerance-associated markers that can modulate the proliferation and function of immune cells. Notably, platelets also expressed embryonic stem cell- and pancreatic islet β-cell-associated markers that are encoded by mitochondrial DNA. Using freshly-isolated human pancreatic islets, ex vivo studies established that platelet-releasing mitochondria can migrate to pancreatic islets and be taken up by islet β cells, leading to the proliferation and enhancement of islet β-cell functions. These findings reveal new mechanisms underlying SCE therapy and open up new avenues to improve the treatment of diabetes in clinics. Stem Cells Translational Medicine 2017.

Concepts: Insulin, Diabetes mellitus type 2, Diabetes mellitus, Mitochondrion, Stem cell, Diabetes mellitus type 1, Islets of Langerhans, Embryonic stem cell

142

The popularity of adipose-derived cell therapy has increased over the last decade, and the number of studies published annually is growing. However, concerns regarding safety in the setting of previous malignancy or the use of allogeneic cells have been raised. We therefore aimed to systematically review all clinical studies using adipose-derived cell therapy to identify reported adverse events with a special focus on risk of thromboembolic, immunological and oncological safety concerns. Our systematic search resulted in 70 included studies involving more than 1,400 patients that were treated with adipose-derived cell therapy. Safety assessment method was not described in 32 of the included studies. For studies involving systemic or cardiac administration, one case of pulmonary thromboembolism and cases of both myocardial and cerebral infarctions were described. In the setting of allogeneic cell therapy studies, where the production of specific antibodies towards donor cells was examined, it was noted that 19%-34% of patients develop antibodies, but the consequence of this is unknown. With regards to oncological safety, only one case of breast cancer recurrence was identified out of 121 patients. Adipose-derived cell therapy has so far shown a favourable safety profile, but safety assessment description has, in general, been of poor quality, and only adverse events that are looked for will be found. We encourage future studies to maintain a strong focus on the safety profile of cell therapy, so its safeness can be confirmed. Stem Cells Translational Medicine 2017.

Concepts: Medicine, Clinical trial, Cancer, Stem cell, Heart, Pharmaceutical industry, Clinical research, Adverse event

139

Extreme prematurity is the leading cause of death among children under 5 years of age. Currently, there is no treatment for bronchopulmonary dysplasia (BPD), the most common complication of extreme prematurity. Experimental studies in animal models of BPD suggest that mesenchymal stromal cells (MSCs) are lung protective. To date, no systematic review and meta-analysis has evaluated the preclinical evidence of this promising therapy. Our protocol was registered with Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies prior to searching MEDLINE (1946 to June 1, 2015), Embase (1947 to 2015 Week 22), Pubmed, Web of Science, and conference proceedings (1990 to present) for controlled comparative studies of neonatal animal models that received MSCs or cell free MSC-derived conditioned media (MSC-CM). Lung alveolarization was the primary outcome. We used random effects models for data analysis and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines. We screened 990 citations; 25 met inclusion criteria. All used hyperoxia-exposed neonatal rodents to model BPD. MSCs significantly improved alveolarization (Standardized mean difference of -1.330, 95% Confidence interval [CI -1.724, -0.94, I(2) 69%]), irrespective of timing of treatment, source, dose, or route of administration. MSCs also significantly ameliorated pulmonary hypertension, lung inflammation, fibrosis, angiogenesis, and apoptosis. Similarly, MSC-CM significantly improved alveolarization, angiogenesis, and pulmonary artery remodeling. MSCs, tested exclusively in hyperoxic rodent models of BPD, show significant therapeutic benefit. Unclear risk of bias and incomplete reporting in the primary studies highlights nonadherence to reporting standards. Overall, safety and efficacy in other species/large animal models may provide useful information for guiding the design of clinical trials. Stem Cells Translational Medicine 2017.

Concepts: Stem cell, Mesenchymal stem cell, Heart, Evidence-based medicine, Systematic review, Pulmonary artery, Meta-analysis, Stromal cell

135

Endothelial cells (ECs) play a key role in revascularization within regenerating tissue. Stem cells are often used as an alternative cell source when ECs are not available. Several cell types have been used to give rise to ECs, such as umbilical cord vessels, or differentiated from somatic stem cells, embryonic, or induced pluripotent stem cells. However, the latter carry the potential risk of chronic immune rejection and oncogenesis. Autologous endothelial precursors are an ideal resource, but currently require an invasive procedure to obtain them from the patient’s own blood vessels or bone marrow. Thus, the goal of this study was to determine whether urine-derived stem cells (USCs) could differentiate into functional ECs in vitro. Urine-derived cells were then differentiated into cells of the endothelial lineage using endothelial differentiation medium for 14 days. Changes in morphology and ultrastructure, and functional endothelial marker expression were assessed in the induced USCs in vitro. Grafts of the differentiated USCs were then subcutaneously injected into nude mice. Induced USCs expressed significantly higher levels of specific markers of ECs (CD31, vWF, eNOS) in vitro and in vivo, compared to nondifferentiated USCs. In addition, the differentiated USC formed intricate tubular networks and presented similar tight junctions, and migration and invasion ability, as well as ability to produce nitric oxide (NO) compared to controls. Using USCs as autologous EC sources for vessel, tissue engineering strategies can yield a sufficient number of cells via a noninvasive, simple, and low-cost method suitable for rapid clinical translation. Stem Cells Translational Medicine 2018.

120

Novel interventions that reestablish endogenous insulin secretion and thereby halt progressive end-organ damage and prolong survival of patients with autoimmune Type 1 diabetes mellitus (T1DM) are urgently needed. While this is currently accomplished with allogeneic pancreas or islet transplants, their utility is significantly limited by both the scarcity of organ donors and life-long need for often-toxic antirejection drugs. Coadministering islets with bone marrow-derived mesenchymal stem cells (MSCs) that exert robust immune-modulating, anti-inflammatory, anti-apoptotic, and angiogenic actions, improves intrahepatic islet survival and function. Encapsulation of insulin-producing cells to prevent immune destruction has shown both promise and failures. Recently, stem cell-derived insulin secreting β-like cells induced euglycemia in diabetic animals, although their clinical use would still require encapsulation or anti-rejection drugs. Instead of focusing on further improvements in islet transplantation, we demonstrate here that the intraperitoneal administration of islet-sized “Neo-Islets” (NIs), generated by in vitro coaggregation of allogeneic, culture-expanded islet cells with high numbers of immuno-protective and cyto-protective MSCs, resulted in their omental engraftment in immune-competent, spontaneously diabetic nonobese diabetic (NOD) mice. This achieved long-term glycemic control without immunosuppression and without hypoglycemia. In preparation for an Food and Drug Administration-approved clinical trial in dogs with T1DM, we show that treatment of streptozotocin-diabetic NOD/severe combined immunodeficiency mice with identically formed canine NIs produced durable euglycemia, exclusively mediated by dog-specific insulin. We conclude that this novel technology has significant translational relevance for canine and potentially clinical T1DM as it effectively addresses both the organ donor scarcity (>80 therapeutic NI doses/donor pancreas can be generated) and completely eliminates the need for immunosuppression. Stem Cells Translational Medicine 2017.

Concepts: Insulin, Diabetes mellitus, Diabetes mellitus type 1, Islets of Langerhans, Glucagon, Pancreas, Diabetes, Organ transplant

114

Recent reports have indicated human embryonic stem cells-derived midbrain dopamine (mDA) neurons as proper cell resources for use in Parkinson’s disease (PD) therapy. Nevertheless, no detailed and systematic study has been conducted to identify which differentiation stages of mDA cells are most suitable for transplantation in PD therapy. Here, we transplanted three types of mDA cells, DA progenitors (differentiated in vitro for 16 days [D16]), immature DA neurons (D25), and DA neurons (D35), into PD mice and found that all three types of cells showed high viability and strong neuronal differentiation in vivo. Both D25 and D35 cells showed neuronal maturation and differentiation toward TH(+) cells and, accordingly, satisfactory behavioral functional recovery. However, transplanted D16 cells were less capable of producing functional recovery. These findings provide a valuable guideline for standardizing the differentiation stage of the transplantable cells used in clinical cell therapy for PD. Stem Cells Translational Medicine 2017.

Concepts: Neuron, Stem cell, Cellular differentiation, Parkinson's disease, Embryonic stem cell, Substantia nigra, Neurotransmitter, Dopamine

113

In this study, we engineered mesenchymal stem cells (MSCs) to over-express basic fibroblast growth factor (bFGF) and evaluated its effects on fracture healing. Adipose-derived mouse MSCs were transduced to express bFGF and green fluorescence protein (ADSC(bFGF) -GFP). Closed-femoral fractures were performed with osterix-mCherry reporter mice of both sexes. The mice received 3 × 10(5) ADSCs transfected with control vector or bFGF via intramuscular injection within or around the fracture sites. Mice were euthanized at days 7, 14, and 35 to monitor MSC engraftment, osteogenic differentiation, callus formation, and bone strength. Compared to ADSC culture alone, ADSC(bFGF) increased bFGF expression and higher levels of bFGF and vascular endothelial growth factor (VEGF) in the culture supernatant for up to 14 days. ADSC(bFGF) treatment increased GFP-labeled MSCs at the fracture gaps and these cells were incorporated into the newly formed callus. quantitative reverse transcription polymerase chain reaction (qRT-PCR) from the callus revealed a 2- to 12-fold increase in the expression of genes associated with nervous system regeneration, angiogenesis, and matrix formation. Compared to the control, ADSC(bFGF) treatment increased VEGF expression at the periosteal region of the callus, remodeling of collagen into mineralized callus and bone strength. In summary, MSC(bFGF) accelerated fracture healing by increasing the production of growth factors that stimulated angiogenesis and differentiation of MSCs to osteoblasts that formed new bone and accelerated fracture repair. This novel treatment may reduce the time required for fracture healing. Stem Cells Translational Medicine 2017.

Concepts: DNA, Gene, Gene expression, Polymerase chain reaction, Molecular biology, Angiogenesis, Mesenchymal stem cell, Cellular differentiation

112

The aim of this exploratory study was to assess the safety and clinical effects of autologous umbilical cord blood (AUCB) infusion in children with idiopathic autism spectrum disorder (ASD). Twenty-nine children 2 to 6 years of age with a confirmed diagnosis of ASD participated in this randomized, blinded, placebo-controlled, crossover trial. Participants were randomized to receive AUCB or placebo, evaluated at baseline, 12, and 24 weeks, received the opposite infusion, then re-evaluated at the same time points. Evaluations included assessments of safety, Expressive One Word Picture Vocabulary Test, 4th edition, Receptive One Word Picture Vocabulary Test, 4th edition, Clinical Global Impression, Stanford-Binet Fluid Reasoning and Knowledge, and the Vineland Adaptive Behavior and Socialization Subscales. Generalized linear models were used to assess the effects of the response variables at the 12- and 24-week time periods under each condition (AUCB, placebo). There were no serious adverse events. There were trends toward improvement, particularly in socialization, but there were no statistically significant differences for any endpoints. The results of this study suggest that autologous umbilical cord infusions are safe for children with ASD. Tightly controlled trials are necessary to further progress the study of AUCB for autism. Stem Cells Translational Medicine 2018.

Concepts: Pharmacology, Clinical trial, Crossover study, Clinical research, Umbilical cord, Cord blood, Wharton's jelly, Autism spectrum