Electroacupuncture Promotes the Survival of the Grafted Human MGE Neural Progenitors in Rats with Cerebral Ischemia by Promoting Angiogenesis and Inhibiting Inflammation.

Stem cells have the potential as a regenerative therapy for cerebral ischemia by improving functional outcomes. However, cell transplantation has some limitations, including a low rate of the grafted cell survival. There is still a major challenge of promoting the harmonious symbiosis between grafted cells and the host. Acupuncture can effectively improve the functional outcome after cerebral ischemia. The present study evaluated the therapeutic effects and explored the mechanism of combined medial ganglionic eminence (MGE) neural progenitors differentiated from human embryonic stem cells (hESCs) with electroacupuncture (EA) in a bilateral common carotid artery occlusion (2VO) rat model. The results showed that EA could promote the survival of the grafted MGE neural progenitors differentiated from hESCs and alleviate learning and memory impairment in rats with cerebral ischemia. This may have partially resulted from inhibited expression of TNF-α and IL-1ß and increased vascular endothelial growth factor (VEGF) expression and blood vessel density in the hippocampus. Our findings indicated that EA could promote the survival of the grafted MGE neural progenitors and enhance transplantation therapy's efficacy by promoting angiogenesis and inhibiting inflammation.

Emerging biological therapies for the treatment of age-related macular degeneration.

INTRODUCTION: Age-related macular degeneration (AMD) is the leading cause of blindness in individuals over age 50 in developed countries. Current therapy for nonexudative AMD (neAMD) is aimed at modifying risk factors and vitamin supplementation to slow progression, while intravitreal anti-vascular endothelial factor (VEGF) injections are the mainstay for treatment of choroidal neovascularization in exudative AMD (eAMD). AREAS COVERED: Over the past decade, promising therapies have emerged that aim to improve the current standard of care for both diseases. Clinical trials for neAMD are investigating targets in the complement cascade, vitamin A metabolism, metformin, and tetracycline, whereas clinical trials for eAMD are aiming to decrease treatment burden through novel port delivery systems, increasing drug half-life, and targeting new sites of the VEGF cascade. Stem cell and gene therapy are also being evaluated for treatment of neAMD and eAMD. EXPERT OPINION: With an aging population, the need for effective, long term, low burden treatment options for AMD will be in increasingly high demand. Current investigations aim to address the shortcomings of current treatment options with breakthrough treatment approaches. Therapeutics in the pipeline hold promise for improving the treatment of AMD, and are on track for widespread use within the next decade.

iPSCs: A Preclinical Drug Research Tool for Neurological Disorders.

The development and commercialization of new drugs is an articulated, lengthy, and very expensive process that proceeds through several steps, starting from target identification, screening new leading compounds for testing in preclinical studies, and subsequently in clinical trials to reach the final approval for therapeutic use. Preclinical studies are usually performed using both cell cultures and animal models, although they do not completely resume the complexity of human diseases, in particular neurodegenerative conditions. To this regard, stem cells represent a powerful tool in all steps of drug discovery. The recent advancement in induced Pluripotent Stem Cells (iPSCs) technology has opened the possibility to obtain patient-specific disease models for drug screening and development. Here, we report the use of iPSCs as a disease model for drug development in the contest of neurological disorders, including Alzheimer's (AD) and Parkinson's disease (PD), Amyotrophic lateral Sclerosis (ALS), and Fragile X syndrome (FRAX).

Mini-Review: Induced pluripotent stem cells and the search for new cell-specific ALS therapeutic targets.

Amongst the most important discoveries in ALS pathobiology are the works demonstrating that multiple cell types contribute to disease onset and progression. However, a significant limitation in ALS research is the inability to obtain tissues from ALS patient brain and spinal cord during the course of the disease. In vivo modeling has provided insights into the role of these cell subtypes in disease onset and progression. However, in vivo models also have shortcomings, including the reliance on a limited number of models based upon hereditary forms of the disease. Therefore, using human induced pluripotent stem cells (iPSC) reprogrammed from somatic cells of ALS patients, with both hereditary and sporadic forms of the disease, and differentiated into cell subtypes of both the central nervous system (CNS) and peripheral nervous system (PNS), have become powerful complementary tools for investigating basic mechanisms of disease as well as a platform for drug discovery. Motor neuron and other neuron subtypes, as well as non-neuronal cells have been differentiated from human iPSC and studied for their potential contributions to ALS pathobiology. As iPSC technologies have advanced, 3D modeling with multicellular systems organised in microfluidic chambers or organoids are the next step in validating the pathways and therapeutic targets already identified. Precision medicine approaches with iPSC using either traditional strategies of screening drugs that target a known pathogenic mechanism as well as "blind-to-target" drug screenings that allow for patient stratification based on drug response rather than clinical characteristics are now being employed.

Stem cell therapy for COVID-19: Possibilities and challenges.

Since its eruption in China, novel coronavirus disease (COVID-19) has been reported in most of the countries and territories (>200) of the world with ∼18 million confirmed cases (as of August 3, 2020). In most of the countries, COVID-19 upsurge is uncontrolled with a significant mortality rate. Currently, no treatment effective for COVID-19 is available in the form of vaccines or antiviral drugs and patients are currently treated symptomatically. Although the majority of the patients develop mild symptoms and recover without mechanical ventilation for respiratory management, severe respiratory illness develops in a significant portion of affected patients and may result in death. While the scientific community is working to develop vaccines and drugs against the COVID-19 pandemic, novel alternative therapies may reduce the mortality rate. Recent use of stem cells for critically ill COVID-19 patients in a small group of patients in China and subsequent Emergency Use Authorization of stem cells by Food and Drug Administration to Global Institute of Stem Cell Therapy and Research and Athersys has created excitement among the medical community. As a result, several clinical trials have been registered using stem cells for COVID-19 treatment that aim to use different cell sources, dosage, and importantly diverse targeted patient groups. In this brief review, the possibilities of stem cell use in COVID-19 patients and relevant challenges in their use have been discussed.

Safety and efficacy assessment of allogeneic human dental pulp stem cells to treat patients with severe COVID-19: structured summary of a study protocol for a randomized controlled trial (Phase I / II).

OBJECTIVES: To assess the safety and therapeutic effects of allogeneic human dental pulp stem cells (DPSCs) in treating severe pneumonia caused by COVID-19. TRIAL DESIGN: This is a single centre, two arm ratio 1:1, triple blinded, randomized, placebo-controlled, parallel group, clinical trial. PARTICIPANTS: Twenty serious COVID-19 cases will be enrolled in the trial from April 6th to December 31st 2020. INCLUSION CRITERIA: hospitalised patients at Renmin Hospital of Wuhan University satisfy all criteria as below: 1)Adults aged 18-65 years;2)Voluntarily participate in this clinical trial and sign the "informed consent form" or have consent from a legal representative.3)Diagnosed with severe pneumonia of COVID-19: nucleic acid test SARS-CoV-2 positive; respiratory distress (respiratory rate > 30 times / min); hypoxia (resting oxygen saturation < 93% or arterial partial pressure of oxygen / oxygen concentration < 300 mmHg).4)COVID-19 featured lung lesions in chest X-ray image. EXCLUSION CRITERIA: Patients will be excluded from the study if they meet any of the following criteria. 1.Patients have received other experimental treatment for COVID-19 within the last 30 days;2.Patients have severe liver condition (e.g., Child Pugh score >=C or AST> 5 times of the upper limit);3.Patients with severe renal insufficiency (estimated glomerular filtration rate <=30mL / min/1.73 m2) or patients receiving continuous renal replacement therapy, hemodialysis, peritoneal dialysis;4.Patients who are co-infected with HIV, hepatitis B, tuberculosis, influenza virus, adenovirus or other respiratory infection viruses;5.Female patients who have no sexual protection in the last 30 days prior to the screening assessment;6.Pregnant or lactating women or women using estrogen contraception;7.Patients who are planning to become pregnant during the study period or within 6 months after the end of the study period;8.Other conditions that the researchers consider not suitable for participating in this clinical trial. INTERVENTION AND COMPARATOR: There will be two study groups: experimental and control. Both will receive all necessary routine treatment for COVID-19. The experimental group will receive an intravenous injection of dental pulp stem cells suspension (3.0x107 human DPSCs in 30ml saline solution) on day 1, 4 and 7; The control group will receive an equal amount of saline (placebo) on the same days. Clinical and laboratory observations will be performed for analysis during a period of 28 days for each case since the commencement of the study. MAIN OUTCOMES: 1. Primary outcome The primary outcome is Time To Clinical Improvement (TTCI). By definition, TTCI is the time (days) it takes to downgrade two levels from the following six ordered grades [(grade 1) discharge to (grade 6) death] in the clinical state of admission to the start of study treatments (hDPSCs or placebo). Six grades of ordered variables: GradeDescriptionGrade 1:Discharged of patient;Grade 2:Hospitalized without oxygen supplement;Grade 3:Hospitalized, oxygen supplement is required, but NIV / HFNC is not required;Grade 4:Hospitalized in intensive care unit, and NIV / HFNC treatment is required;Grade 5:Hospitalized in intensive care unit, requiring ECMO and/or IMV;Grade 6:Death. ABBREVIATIONS: NIV, non-invasive mechanical ventilation; HFNC, high-flow nasal catheter; IMV, invasive mechanical ventilation. 2. Secondary outcomes 2.1 vital signs: heart rate, blood pressure (systolic blood pressure, diastolic blood pressure). During the screening period, hospitalization every day (additional time points of D1, D4, D7 30min before injection, 2h ± 30min, 24h ± 30min after the injection) and follow-up period D90 ± 3 days. 2.2 Laboratory examinations: during the screening period, 30 minutes before D1, D4, D7 infusion, 2h ± 30min, 24h ± 30min after the end of infusion, D10, D14, D28 during hospitalization or discharge day and follow-up period D90 ± 3 days. 2.3 Blood routine: white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, basophils, neutrophils, lymphocytes, monocytes, eosinophils Acidic granulocyte count, basophil count, red blood cell, hemoglobin, hematocrit, average volume of red blood cells, average red blood cell Hb content, average red blood cell Hb concentration, RDW standard deviation, RDW coefficient of variation, platelet count, platelet specific platelet average Volume, platelet distribution width,% of large platelets; 2.4 Liver and kidney function tests: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyl transferase, prealbumin, total protein, albumin, globulin, white / globule ratio , Total bilirubin, direct bilirubin, cholinesterase, urea, creatinine, total carbon dioxide, uric acid glucose, potassium, sodium, chlorine, calcium, corrected calcium, magnesium, phosphorus, calcium and phosphorus product, anion gap, penetration Pressure, total cholesterol, triacylglycerol, high density lipoprotein cholesterol, Low density lipoprotein cholesterol, lipoprotein a, creatine kinase, lactate dehydrogenase, estimated glomerular filtration rate. 2.5 Inflammation indicators: hypersensitive C-reactive protein, serum amyloid (SAA); 2.6 Infectious disease testing: Hepatitis B (HBsAg, HBsAb, HBeAg, HBeAb, HBcAb), Hepatitis C (Anti-HCV), AIDS (HIVcombin), syphilis (Anti-TP), cytomegalovirus CMV-IgM, cytomegalovirus CMV-IgG; only during the screening period and follow-up period D90 ± 3. 2.7 Immunological testing: Collect peripheral blood to detect the phenotype of T lymphocyte, B lymphocyte, natural killer cell, Macrophage and neutrophil by using flow cytometry. Collect peripheral blood to detect the gene profile of mononuclear cells by using single-cell analyses. Collect peripheral blood serum to detect various immunoglobulin changes: IgA, IgG, IgM, total IgE; Collect peripheral blood serum to explore the changes of cytokines, Th1 cytokines (IL-1 ß, IL-2, TNF-a, ITN-γ), Th2 cytokines (IL-4, IL-6, IL -10). 2.8 Pregnancy test: blood ß-HCG, female subjects before menopause are examined during the screening period and follow-up period D90 ± 3. 2.9 Urine routine: color, clarity, urine sugar, bilirubin, ketone bodies, specific gravity, pH, urobilinogen, nitrite, protein, occult blood, leukocyte enzymes, red blood cells, white blood cells, epithelial cells, non-squamous epithelial cells , Transparent cast, pathological cast, crystal, fungus; 2.10 Stool Routine: color, traits, white blood cells, red blood cells, fat globules, eggs of parasites, fungi, occult blood (chemical method), occult blood (immune method), transferrin (2h ± 30min after the injection and not detected after discharge). RANDOMIZATION: Block randomization method will be applied by computer to allocate the participants into experimental and control groups. The random ratio is 1:1. BLINDING (MASKING): Participants, outcomes assessors and investigators (including personnel in laboratory and imaging department who issue the sample report or image observations) will be blinded. Injections of cell suspension and saline will be coded in accordance with the patient's randomisation group. The blind strategy is kept by an investigator who does not deliver the medical care or assess primary outcome results. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): Twenty participants will be randomized to the experimental and control groups (10 per group). TRIAL STATUS: Protocol version number, hDPSC-CoVID-2019-02-2020 Version 2.0, March 13, 2020. Patients screening commenced on 16th April and an estimated date of the recruitment of the final participants will be around end of July. . TRIAL REGISTRATION: Registration: World Health Organization Trial Registry: ChiCTR2000031319; March 27,2020. ClinicalTrials.gov Identifier: NCT04336254; April 7, 2020 Other Study ID Numbers: hDPSC-CoVID-2019-02-2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Procedural Treatments for Knee Osteoarthritis: A Review of Current Injectable Therapies.

Knee osteoarthritis is a common painful degenerative condition affecting the aging Canadian population. In addition to pain and disability, osteoarthritis is associated with depression, comorbid conditions such as diabetes, and increased caregiver burden. It is predicted to cost the Canadian healthcare system $7.6 billion dollars by 2031. Despite its high cost and prevalence, controversy persists in the medical community regarding optimal therapies to treat knee osteoarthritis. A variety of medications like nonsteroidal anti-inflammatories and opioids can cause severe side effects with limited benefits. Total knee arthroplasty, although a definitive management, comes with risk such as postoperative infections, revisions, and chronic pain. Newer injectable therapies are gaining attention as alternatives to medications because of a safer side effect profile and are much less invasive than a joint replacement. Platelet-rich plasma is beginning to replace the more common injectable therapies of intra-articular corticosteroids and hyaluronic acid, but larger trials are needed to confirm this effect. Small studies have examined prolotherapy and stem cell therapy and demonstrate some benefits. Trials involving genicular nerve block procedures have been successful. As treatments evolve, injectable therapies may offer a safe and effective pathway for patients suffering from knee osteoarthritis.

Combined therapy of photobiomodulation and adipose-derived stem cells synergistically improve healing in an ischemic, infected and delayed healing wound model in rats with type 1 diabetes mellitus.

OBJECTIVE: We assessed the therapeutic effects of photobiomodulation (PBM) and adipose-derived stem cell (ADS) treatments individually and together on the maturation step of repairing of a delayed healing wound model in rats with type 1 diabetes mellitus (DM1). RESEARCH DESIGN AND METHODS: We randomly assigned 24 rats with DM1 to four groups (n=6 per group). Group 1 was the control (placebo) group. In group 2, allograft human ADSs were transplanted. Group 3 was subjected to PBM (wavelength: 890 nm, peak power output: 80 W, pulse frequency: 80 Hz, pulsed duration: 180 ns, duration of exposure for each point: 200 s, power density: 0.001 W/cm2, energy density: 0.2 J/cm2) immediately after surgery, which continued for 6 days per week for 16 days. Group 4 received both the human ADS and PBM. In addition, we inflicted an ischemic, delayed healing, and infected wound simulation in all of the rats. The wounds were infected with methicillin-resistant Staphylococcus aureus (MRSA). RESULTS: All three treatment regimens significantly decreased the amount of microbial flora, significantly increased wound strength and significantly modulated inflammatory response and significantly increased angiogenesis on day 16. Microbiological analysis showed that PBM+ADS was significantly better than PBM and ADS alone. In terms of wound closure rate and angiogenesis, PBM+ADS was significantly better than the PBM, ADS and control groups. CONCLUSIONS: Combination therapy of PBM+ADS is more effective that either PBM or ADS in stimulating skin injury repair, and modulating inflammatory response in an MRSA-infected wound model of rats with DM1.

Prophylaxis and management of graft versus host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation.

Graft-versus-host disease (GVHD) is a major factor contributing to mortality and morbidity after allogeneic stem-cell transplantation. Because of the small number of results from well designed, large-scale, clinical studies there is considerable variability in the prevention and treatment of GVHD worldwide. In 2014, to standardise treatment approaches the European Society of Blood and Marrow Transplantation published recommendations on the management of GVHD in the setting of HLA-identical sibling or unrelated donor transplantation in adult patients with haematological malignancies. Here we update these recommendations including the results of study published after 2014. Evidence was searched in three steps: first, a widespread scan of published trials, meta-analyses, and systematic reviews; second, expert opinion was added for specific issues following several rounds of debate; and third, a refined search to target debated or rapidly updating issues. On the basis of this evidence and the 2014 recommendations, five members of the EBMT Transplant Complications Working Party created 38 statements on GVHD prophylaxis, drug management, and treatment of acute and chronic GVHD. Subsequently, they created the EBMT GVHD management recommendation expert panel by recruiting 20 experts with expertise in GVHD management. An email-based, two-round Delphi panel approach was used to manage the consensus. Modified National Comprehensive Cancer Network categories for evidence and consensus were applied to the approved statements. We reached 100% consensus for 29 recommendations and 95% consensus for nine recommendations. Key updates to these recommendations include a broader use of rabbit anti-T-cell globulin; lower steroid doses for the management of grade 2 acute GVHD with isolated skin or upper gastrointestinal tract manifestations; fluticasone, azithromycin, and montelukast should be used for bronchiolitis obliterans syndrome; and the addition of newer treatment options for resteroid-refractory acute and chronic GVHD. In addition, we discuss specific aspects of GVHD prophylaxis and management in the setting of haploidentical transplantation and in paediatric patients, but no formal recommendations on those procedures have been provided in this Review. The European Society of Blood and Marrow Transplantation proposes to use these recommendations as a basis for the routine management of GVHD during stem-cell transplantation.

Biomaterials and Magnetic Stem Cell Delivery in the Treatment of Spinal Cord Injury.

Spinal cord injury (SCI) is a serious trauma, which often results in a permanent loss of motor and sensory functions, pain and spasticity. Despite extensive research, there is currently no available therapy that would restore the lost functions after SCI in human patients. Advanced treatments use regenerative medicine or its combination with various interdisciplinary approaches such as tissue engineering or biophysical methods. This review summarizes and critically discusses the research from specific interdisciplinary fields in SCI treatment such as the development of biomaterials as scaffolds for tissue repair, and using a magnetic field for targeted cell delivery. We compare the treatment effects of synthetic non-degradable methacrylate-based hydrogels and biodegradable biological scaffolds based on extracellular matrix. The systems using magnetic fields for magnetically guided delivery of stem cells loaded with magnetic nanoparticles into the lesion site are then suggested and discussed.

Fidelity of long-term cryopreserved adipose-derived stem cells for differentiation into cells of ocular and other lineages.

Adipose-Derived Stem Cells (ADSCs) have an important contribution in regenerative medicine ranging from testing stem cell therapy for disease treatment in pre-clinical models to clinical trials. For immediate use of stem cells for therapy, there is a requirement of the high dose of stem cells at different time points which can be met by cryopreservation. In this study, we evaluated the characteristics of long-term cryopreserved ADSCs and their regenerative potential after an average of twelve-year cryopreservation. Revived ADSCs were examined for cell viability and proliferation by trypan blue, Calcein/Hoechst and MTT assay. Expression of stem cell markers was examined by flow cytometry, immunostaining and qPCR. Colony forming efficiency and spheroid formation ability were also assessed. Multilineage differentiation potential was evaluated by induction into osteocytes, adipocytes, neural cells, corneal keratocytes and trabecular meshwork (TM) cells. Post-thaw, ADSCs maintained expression of stem cell markers CD90, CD73, CD105, CD166, NOTCH1, STRO-1, ABCG2, OCT4, KLF4. ADSCs retained colony and spheroid forming potential. These cells were able to differentiate into osteocytes, confirmed by Alizarin Red S staining and elevated expression of osteocalcin and osteopontin; into adipocytes by Oil Red O staining and elevated expression of PPARγ2. ADSCs could differentiate into neural cells, stained positive to ß-III tubulin, neurofilament, GFAP as well as elevated expression of nestin and neurofilament mRNAs. ADSCs could also give rise to corneal keratocytes expressing keratocan, keratan sulfate, ALDH and collagen V, and to TM cells expressing CHI3L1 and AQP1. Differentiated TM cells responded to dexamethasone treatment with increased Myocilin expression, which could be used as in vitro glaucoma model for further studies. Conditioned medium from ADSCs was found to impart a regenerative effect on primary TM cells. In conclusion, ADSCs maintained their stemness and multipotency after long-term cryopreservation with variability between different donors. This study can have great repercussions in regenerative medicine and pave the way for future clinical trials using cryopreserved ADSCs.

The impact of iron chelation therapy on patients with lower/intermediate IPSS MDS and the prognostic role of elevated serum ferritin in patients with MDS and AML: A meta-analysis.

Serum ferritin (SF) has been identified as a potential prognostic factor for patients undergoing stem cell transplantation, but the prognostic value of SF in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients and the impact of iron chelation therapy (ICT) on MDS patients are controversial. The present meta-analysis aimed to better elucidate these relationships.Three electronic databases were searched systematically to identify reports on the prognostic role of SF in MDS and AML patients, and those investigating the impact of ICT on prognosis of MDS patients. The hazard ratios (HRs) and its 95% confidence interval (95%CI) were extracted from the identified studies using Cox proportional hazard regression model for overall survival (OS) and progression of MDS to AML.Twenty reports including 1066 AML patients and 4054 MDS patients were included in present study. The overall pooled HRs for OS of AML and MDS patients with elevated SF prior to transplantation was 1.73 (1.40-2.14), subgroup analyses stratified by the cut-off value of SF ≥1400/1000 ng/mL showed that the pooled HRs were 1.45 (0.98-2.15) and 1.65 (1.30-2.10), respectively. The pooled HRs for ICT in MDS patients was 0.30 (0.23-0.40). For ICT, the pooled HRs for the progression of MDS to AML was 0.84 (0.61-1.61).SF has a negative impact on the OS of AML and MDS patients when it is higher than 1000 ng/mL. ICT can improve the OS of MDS patients with iron overload but it is not associated with the progression of MDS to AML.

Evaluation of autologous adipose-derived stem cells vs. fractional carbon dioxide laser in the treatment of post acne scars: a split-face study.

BACKGROUND: Scarring is a distressing outcome of acne, as it causes cosmetic and psychological problems to the patients. Unfortunately no single treatment is satisfactory; instead, employing multiple modalities may have better outcome. Autologous adipose tissue-derived adult stem cells (AT-ASCs) and their secretory factors can stimulate collagen synthesis; angiogenesis and migration of fibroblasts thus regenerate damaged tissues. Also, conventional treatments for acne scarring, such as lasers and topical regimens, induce new collagen synthesis via activation of dermal fibroblasts or growth factors. The aim of the study was to verify the effectiveness of AT-ASCs for the treatment of acne scarring vs. the fractional carbon dioxide laser (FxCR). SUBJECTS AND METHODS: Split face comparative study included 10 adult patients with post-acne scars on both sides of the face. One side received AT-ASCs single injection while the other received three sessions of FxCR. Scars were then assessed using the global scoring system Goodman and Baron, scar area percent using NIH ImageJ software and functional assessment by measuring the transepidermal water loss (TEWL) and skin hydration. Both sides were followed for three months. RESULTS: A significant improvement in the degree of scar severity, scar area percent, skin hydration, and TEWL after 3 months of treatment on both sides of the face with insignificant differences between both treatment modalities, provided that AT-ASCs treatment was employed once vs. three sessions of FxCR. CONCLUSION: One injection of AT-ASCs is as effective as three sessions of FxCR in the treatment of atrophic acne scars.

Molecular-Based Treatment Strategies for Osteoporosis: A Literature Review.

Osteoporosis is an unavoidable public health problem in an aging or aged society. Anti-resorptive agents (calcitonin, estrogen, and selective estrogen-receptor modulators, bisphosphonates, anti-receptor activator of nuclear factor κB ligand antibody along with calcium and vitamin D supplementations) and anabolic agents (parathyroid hormone and related peptide analogs, sclerostin inhibitors) have major roles in current treatment regimens and are used alone or in combination based on the pathological condition. Recent advancements in the molecular understanding of bone metabolism and in bioengineering will open the door to future treatment paradigms for osteoporosis, including antibody agents, stem cells, and gene therapies. This review provides an overview of the molecular mechanisms, clinical evidence, and potential adverse effects of drugs that are currently used or under development for the treatment of osteoporosis to aid clinicians in deciding how to select the best treatment option.

Road Map for Development of Stem Cell-Based Alternative Test Methods.

Much progress has been made in establishing strategies for differentiation of induced human pluripotent stem cells (hiPSCs). However, differentiated hiPSCs are not yet routinely used for prediction of toxicity. Here, limiting factors are summarised and possibilities for improvement are discussed, with a focus on hepatocytes, cardiomyocytes, tubular epithelial cells, and developmental toxicity. Moreover, we make recommendations for further fine-tuning of differentiation protocols for hiPSCs to hepatocyte-like cells by comparing individual steps of currently available protocols to the mechanisms occurring during embryonic development. A road map is proposed to facilitate test system development, including a description of the most useful performance metrics.

Human Platelet Lysate Improves Bone Forming Potential of Human Progenitor Cells Expanded in Microcarrier-Based Dynamic Culture.

Xenogeneic-free media are required for translating advanced therapeutic medicinal products to the clinics. In addition, process efficiency is crucial for ensuring cost efficiency, especially when considering large-scale production of mesenchymal stem cells (MSCs). Human platelet lysate (HPL) has been increasingly adopted as an alternative for fetal bovine serum (FBS) for MSCs. However, its therapeutic and regenerative potential in vivo is largely unexplored. Herein, we compare the effects of FBS and HPL supplementation for a scalable, microcarrier-based dynamic expansion of human periosteum-derived cells (hPDCs) while assessing their bone forming capacity by subcutaneous implantation in small animal model. We observed that HPL resulted in faster cell proliferation with a total fold increase of 5.2 ± 0.61 in comparison to 2.7 ± 02.22-fold in FBS. Cell viability and trilineage differentiation capability were maintained by HPL, although a suppression of adipogenic differentiation potential was observed. Differences in mRNA expression profiles were also observed between the two on several markers. When implanted, we observed a significant difference between the bone forming capacity of cells expanded in FBS and HPL, with HPL supplementation resulting in almost three times more mineralized tissue within calcium phosphate scaffolds. FBS-expanded cells resulted in a fibrous tissue structure, whereas HPL resulted in mineralized tissue formation, which can be classified as newly formed bone, verified by µCT and histological analysis. We also observed the presence of blood vessels in our explants. In conclusion, we suggest that replacing FBS with HPL in bioreactor-based expansion of hPDCs is an optimal solution that increases expansion efficiency along with promoting bone forming capacity of these cells. Stem Cells Translational Medicine 2019;8:810&821.

Tracking Stem Cell Implants in Cartilage Defects of Minipigs by Using Ferumoxytol-enhanced MRI.

Background Cartilage repair outcomes of matrix-associated stem cell implants (MASIs) in patients have been highly variable. Conventional MRI cannot help distinguish between grafts that will and grafts that will not repair the underlying cartilage defect until many months after the repair. Purpose To determine if ferumoxytol nanoparticle labeling could be used to depict successful or failed MASIs compared with conventional MRI in a large-animal model. Materials and Methods Between January 2016 and December 2017, 10 Göttingen minipigs (n = 5 male; n = 5 female; mean age, 6 months ± 5.1; age range, 4-20 months) received implants of unlabeled (n = 12) or ferumoxytol-labeled (n = 20) viable and apoptotic MASIs in cartilage defects of the distal femur. All MASIs were serially imaged with MRI on a 3.0-T imaging unit at week 1 and weeks 2, 4, 8, 12, and 24, with calculation of T2 relaxation times. Cartilage regeneration outcomes were assessed by using the MR observation of cartilage repair tissue (MOCART) score (scale, 0-100), the Pineda score, and histopathologic quantification of collagen 2 production in the cartilage defect. Findings were compared by using the unpaired Wilcoxon rank sum test, a linear regression model, the Fisher exact test, and Pearson correlation. Results Ferumoxytol-labeled MASIs showed significant T2 shortening (22.2 msec ± 3.2 vs 27.9 msec ± 1.8; P < .001) and no difference in cartilage repair outcomes compared with unlabeled control MASIs (P > .05). At week 2 after implantation, ferumoxytol-labeled apoptotic MASIs showed a loss of iron signal and higher T2 relaxation times compared with ferumoxytol-labeled viable MASIs (26.6 msec ± 4.9 vs 20.8 msec ± 5.3; P = .001). Standard MRI showed incomplete cartilage defect repair of apoptotic MASIs at 24 weeks. Iron signal loss at 2 weeks correlated with incomplete cartilage repair, diagnosed at histopathologic examination at 12-24 weeks. Conclusion Ferumoxytol nanoparticle labeling can accelerate the diagnosis of successful and failed matrix-associated stem cell implants at MRI in a large-animal model. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Sneag and Potter in this issue.

An update on biology, diagnosis and treatment of primary plasma cell leukemia.

INTRODUCTION: Primary plasma cell leukemia (PPCL) is one of the most aggressive hematological malignancies. The prognosis of PPCL patients remains poor, although some improvements have been made in recent years. Areas covered: In this review recent clinical and biological advances in PPCL are reported. Some recommendations for the practical management of these patients are provided, with a particular focus on the role of novel agents and transplant procedures. A brief description of the currently ongoing clinical trials with new drugs is also enclosed. Expert opinion: PPCL still represents a difficult challenge for all hematologists. Here the authors provide a personal view on how the current, generally unsatisfactory results in this neoplastic disorder could be improved. In particular, dedicated studies exploring alternative therapies are necessary and eagerly awaited. Such studies should possibly be based on new biological information that could be of help in identifying novel genetic biomarkers for risk stratification and new actionable molecular targets.

Cell Therapy for Ischemic Stroke: How to Turn a Promising Preclinical Research into a Successful Clinical Story.

Stroke is a major public health issue with limited treatment. The pharmacologically or mechanically removing of the clot is accessible to less than 10% of the patients. Stem cell therapy is a promising alternative strategy since it increases the therapeutic time window but many issues remain unsolved. To avoid a new dramatic failure when translating experimental data on the bedside, this review aims to highlight the indispensable checkpoints to make a successful clinical trial based on the current preclinical literature. The large panel of progenitors/ stem cells at the researcher's disposal is to be used wisely, regarding the type of cells, the source of cells, the route of delivery, the time window, since it will directly affect the outcome. Mechanisms are still incompletely understood, although recent studies have focused on the inflammation modulation of most cells types.