• Applications and challenges
• Regenerative medicine
• Stem cell transplantation

• Cell delivery approaches
• Cell therapy
• Coronary heart disease
• Regeneration medicine

• Humans
• Coronary Disease/therapy
• Cell- and Tissue-Based Therapy
• Heart
• Stem Cell Transplantation/methods
• Regenerative Medicine

• Extracellular vesicle
• Regeneration
• Repair
• Retina
• Stem cell
• Therapy

• 2018YFA0107303 Nation Key Technologies Research and Development Program
• 82070990 Natural Science Foundation of China

• complex permittivity spectra
• dielectric spectroscopy
• dielectrophoresis
• immunohistochemistry
• open-ended coaxial probe
• protein
• stem cell

• Humans
• Dielectric Spectroscopy
• Suspensions
• Cell Differentiation

• Apoptosis
• Head injury
• Inflammation
• Nano scaffold
• Stem cell therapy

• bioprocess design
• bioprocess economic modeling
• cell and gene therapy
• quality by design
• stem cell manufacturing

Traumatic brain injury is the main cause of injury-related deaths and disabilities throughout the world, which is characterized by a disruption of the normal physiology of the brain following trauma. It can potentially cause severe complications such as physical, cognitive, and emotional impairment. In addition to understanding traumatic brain injury pathophysiology, this review explains the therapeutic potential of stem cells following brain injury in two pathways: response of endogenous neurogenic cells and transplantation of exogenous stem cell therapy. After traumatic brain injuries, clinical evidence indicated that endogenous neural progenitor cells might play an important role in regenerative medicine to treat brain injury. This is due to an increased neurogenic regeneration ability of these cells following brain injury. Besides, exogenous stem cell transplantation has also accelerated immature neuronal development and increased endogenous cellular proliferation in the damaged brain region. Therefore, a better understanding of the endogenous neural stem cell’s regenerative ability and the effect of exogenous stem cells on proliferation and differentiation ability may help researchers to understand how to increase functional recovery and tissue repair following injury.

• cell transplantation
• endogenous neurogenesis
• neural stem cells
• stem cell therapy
• traumatic brain injury

In aged people, tendon injuries frequently occur during sporting and daily activities. In clinical practice, typical physiotherapeutic, pharmacotherapeutic, and surgical techniques do not result in the full recovery of injured tendons, which may lead to chronic degenerative disease.

We first isolated tendon stem cells (TSCs) from rats and transfected them with the TGFβ1 gene, resulting in TGFβ1-TSCs. The proliferation of TSCs was detected using the Cell Counting Kit 8, and TSCs were identified by immunofluorescence analysis and differentiation capacity analysis. Aggrecan, COL2A1, alpha smooth muscle actin (α-SMA), and p-Smad2 expression levels were detected using western blotting and quantitative reverse transcription polymerase chain reaction. Additionally, a tendon injury model was generated to explore the effect of TGFβ1 on the repair of the tendon by TSCs.

Compared with fibrinogen treatment, TSC + fibrinogen or TGFβ1-TSC + fibrinogen treatment significantly promoted the fibrosis of injured tendons, as evidenced by histological analyses, with TGFβ1-TSC + fibrinogen having a greater effect than TSC + fibrinogen. In TGFβ1-TSCs, increased expression levels of aggrecan and COL2A1 indicated that TGFβ1 signaling induced chondrogenic differentiation. Meanwhile, the increased collagen and α-SMA protein levels indicated that TGFβ1 promoted fibrogenesis. Additionally, TGFβ1 stimulated the production of phosphorylated Smad2 in TSCs, which suggested that the chondrogenic and fibrogenic differentiation of TSCs, as well as tissue regeneration, may be associated with the TGFβ1/Smad2 pathway.

TGFβ1-TSC therapy may be a candidate for effective tendon fibrosis.

• Adipogenesis
• Chondrogenesis
• Osteogenesis
• TGFβ1
• Tendon stem cells

• adipose tissue stromal cells (atMSCs)
• bone marrow MSCs (bmMSC)
• cell-based immune modulation
• mesenchymal stromal/stem cells (MSC)
• placenta-derived mesenchymal stromal cells (hPSCs/pMSCs)
• pro-regenerative effects
• regenerative cell therapy
• xenogeneic cell delivery

• Adipose Tissue/metabolism
• Allografts/metabolism
• Animals
• Bone Marrow/metabolism
• Bone Marrow Cells/metabolism
• Cell Differentiation/physiology
• Cell Proliferation/physiology
• Cell- and Tissue-Based Therapy/methods
• Female
• Humans
• Mesenchymal Stem Cell Transplantation/methods
• Mesenchymal Stem Cells/metabolism
• Placenta/metabolism
• Placenta/physiology
• Pregnancy
• Stromal Cells/metabolism

• 1639/14 Israel Science Foundation

• cardiac repair
• cellular therapy
• ischemic heart disease
• mechanism
• stem cell

This study describes the use of a previously reported chimerised monoclonal antibody (mAb), ch2448, to kill human embryonic stem cells (hESCs) in vivo and prevent or delay the formation of teratomas. ch2448 was raised against hESCs and was previously shown to effectively kill ovarian and breast cancer cells in vitro and in vivo. The antigen target was subsequently found to be Annexin A2, an oncofetal antigen expressed on both embryonic cells and cancer cells. Against cancer cells, ch2448 binds and kills via antibody‐dependent cell‐mediated cytotoxicity (ADCC) and/or antibody‐drug conjugate (ADC) routes. Here, we investigate if the use of ch2448 can be extended to hESC. ch2448 was found to bind specifically to undifferentiated hESC but not differentiated progenitors. Similar to previous study using cancer cells, ch2448 kills hESC in vivo either indirectly by eliciting ADCC or directly as an ADC. The treatment with ch2448 post‐transplantation eliminated the in vivo circulating undifferentiated cells and prevented or delayed the formation of teratomas. This surveillance role of ch2448 adds an additional layer of safeguard to enhance the safety and efficacious use of pluripotent stem cell‐derived products in regenerative medicine. Thereby, translating the use of ch2448 in the treatment of cancers to a proof of concept study in hESC (or pluripotent stem cell [PSC]), we show that mAbs can also be used to eliminate teratoma forming cells in vivo during PSC‐derived cell therapies. We propose to use this strategy to complement existing methods to eliminate teratoma‐forming cells in vitro. Residual undifferentiated cells may escape in vitro removal methods and be introduced into patients together with the differentiated cells.

• antibody-dependent cell-mediated cytotoxicity
• antibody-drug conjugate
• cancer
• human embryonic stem cells
• monoclonal antibody
• pluripotent
• teratoma

• cardiovascular progenitor cells
• embryonic stem cells
• heart failure
• tissue engineering

A low surface expression level of human leukocyte antigen class I (HLA-I) ensures that the mesenchymal stem cells (MSCs) escape from the allogeneic recipients' immunological surveillance. Here, we discovered that both transcriptional and synthesis levels of HLA-I in MSCs increased continuously after interferon (IFN)-γ treatment, whereas interestingly, their surface HLA-I expression was downregulated after reaching an HLA-I surface expression peak. Microarray data indicated that the post-transcriptional process plays an important role in the downregulation of surface HLA-I. Further studies identified that IFN-γ-treated MSCs accelerated HLA-I endocytosis through a clathrin-independent dynamin-dependent endocytosis pathway. Furthermore, cells that have self-downregulated surface HLA-I expression elicit a weaker immune response than they previously could. Thus uncovering the plasticity of MSCs in the regulation of HLA-I surface expression would reveal insights into the membrane transportation events leading to the maintenance of low surface HLA-I expression, providing more evidence for selecting and optimizing low-immunogenic MSCs to improve the therapeutic efficiency.

•

hESC-MSCs have the plasticity of maintaining low HLA-I expression on cell surface

• Biological Sciences
• Cell Biology
• Immunology
• Stem Cells Research

• artificial pancreas
• automated insulin delivery
• continuous glucose monitoring
• encapsulation
• immunosuppression
• stem cells
• type 1 diabetes

• Biomaterials
• Cardiac tissue engineering
• Cells
• Heart failure
• Ischaemic heart disease

• Biomedical Research/standards
• Cardiology/standards
• Consensus
• Heart Failure/pathology
• Heart Failure/physiopathology
• Heart Failure/surgery
• Humans
• Myocardial Ischemia/pathology
• Myocardial Ischemia/physiopathology
• Myocardial Ischemia/surgery
• Myocardium/pathology
• Recovery of Function
• Regeneration
• Stem Cell Transplantation/adverse effects
• Stem Cell Transplantation/standards
• Tissue Engineering/standards
• Treatment Outcome

• FS/10/039/28270 British Heart Foundation
• Department of Health
• PG/16/85/32471 British Heart Foundation
• PG/18/44/33790 British Heart Foundation

• FOXO3
• aging
• gene editing
• stem cell
• vascular cells

Traumatic brain injury (TBI) is a major cause of death worldwide. Depending on the severity of the injury, TBI can reflect a broad range of consequences such as speech impairment, memory disturbances, and premature death. In this study, embryonic neural stem cells (ENSC) were isolated from E14 mouse embryos and cultured to produce neurospheres which were induced to generate differentiated cells (DC). As a cell replacement treatment option, we aimed to transplant ENSC or DC into the adult injured C57BL/6 mouse cortex controlled cortical impact (CCI) model, 7 days post-trauma, in comparison to saline injection (control). The effect of grafted cells on neuroinflammation and neurogenesis was investigated at 1 and 4 weeks post-transplantation. Results showed that microglia were activated following mild CCI, but not enhanced after engraftment of ENSC or DC. Indeed, ipsilateral lesioned somatosensory area expressed high levels of Iba-1+ microglia within the different groups after 1 and 4 weeks. On the other hand, treatment with ENSC or DC demonstrated a significant reduction in astrogliosis. The levels of GFAP expressing astrocytes started decreasing early (1 week) in the ENSC group and then were similarly low at 4 weeks in both ENSC and DC. Moreover, neurogenesis was significantly enhanced in ENSC and DC groups. Indeed, a significant increase in the number of DCX expressing progenitor cells was observed at 1 week in the ENSC group, and in DC and ENSC groups at 4 weeks. Furthermore, the number of mature neuronal cells (NeuN+) significantly increased in DC group at 4 weeks whereas they decreased in ENSC group at 1 week. Therefore, injection of ENSC or DC post-CCI caused decreased astrogliosis and suggested an increased neurogenesis via inducing neural progenitor proliferation and expression rather than neuronal maturation. Thus, ENSC may play a role in replacing lost cells and brain repair following TBI by improving neurogenesis and reducing neuroinflammation, reflecting an optimal environment for transplanted and newly born cells.

• NSC
• TBI
• astrocyte
• cortex
• lesion
• neuron
• neurosphere
• transplantation

• Cell therapy
• Clinical trials
• Drug-based therapy
• Neurotrauma
• Stem cells
• Traumatic brain injury

• Differentiation
• Ectoderm
• Embryoid bodies
• Embryonic stem cells
• Endoderm
• Mesoderm
• Pluripotency

• Cell Differentiation/physiology
• Embryonic Stem Cells/cytology
• Embryonic Stem Cells/metabolism
• Humans
• Membrane Proteins/metabolism
• Nanog Homeobox Protein/biosynthesis
• Nanog Homeobox Protein/genetics
• Nanog Homeobox Protein/metabolism
• Neoplasm Proteins/metabolism
• Nerve Tissue Proteins
• Octamer Transcription Factor-3/biosynthesis
• Octamer Transcription Factor-3/genetics
• Octamer Transcription Factor-3/metabolism
• Pluripotent Stem Cells/cytology
• Pluripotent Stem Cells/metabolism
• Protein Processing, Post-Translational
• Protein Stability
• Proto-Oncogene Proteins c-akt/metabolism
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• SOXB1 Transcription Factors/biosynthesis
• SOXB1 Transcription Factors/genetics
• SOXB1 Transcription Factors/metabolism

• Cell transplantation
• Cognitive function
• Endogenous neurogenesis
• Hippocampus
• Neural stem cells
• Subventricular zone
• Traumatic brain injury

• Adult Stem Cells/cytology
• Adult Stem Cells/metabolism
• Base Sequence
• Carcinogenesis/pathology
• Cells, Cultured
• Gene Editing
• Genetic Enhancement
• Human Embryonic Stem Cells/metabolism
• Humans
• Nucleotides/metabolism

• K99 CA158055 NCI NIH HHS
• R00 CA158055 NCI NIH HHS
• P30 CA086862 NCI NIH HHS
• R01 CA200673 NCI NIH HHS
• R01 CA203834 NCI NIH HHS

Traumatic brain injury (TBI) is a complex condition that presents with a wide spectrum of clinical symptoms caused by an initial insult to the brain through an external mechanical force to the skull. In the United States alone, TBI accounts for more than 50,000 deaths per year and is one of the leading causes of mortality among young adults in the developed world. Pathophysiology of TBI is complex and consists of acute and delayed injury. In the acute phase, brain tissue destroyed upon impact includes neurons, glia, and endothelial cells, the latter of which makes up the blood-brain barrier. In the delayed phase, “toxins” released from damaged cells set off cascades in neighboring cells eventually leading to exacerbation of primary injury. As researches further explore pathophysiology and molecular mechanisms underlying this debilitating condition, numerous potential therapeutic strategies, especially those involving stem cells, are emerging to improve recovery and possibly reverse damage. In addition to elucidating the most recent advances in the understanding of TBI pathophysiology, this review explores two primary pathways currently under investigation and are thought to yield the most viable therapeutic approach for treatment of TBI: manipulation of endogenous neural cell response and administration of exogenous stem cell therapy.

• Cancer risk
• Human embryonic stem cells
• Humanized mice
• Immune protection
• Suicidal genes

• Antibody fragments
• Avidity
• Multimerization
• Self-assembling polypeptides
• hESC therapy
• scFv

• Combination therapy
• Growth factors
• Pathophysiology
• ROCK inhibitors
• Stem cells
• Traumatic brain injury
• Treatment

Herbal Epimedium (HE) has been commonly used as a tonic, antirheumatic agent and in the treatment of bone-associated diseases including osteoporosis. Treatment for osteoporosis is important to increase bone mass density and maintain to balance of bone remodeling. The present study was performed to investigate the effects of HE on mouse bone marrow mesenchymal stem cell (mBMMSC) proliferation and osteogenic differentiation, using MTT assays, proliferating cell nuclear antigen (PCNA) detection and apoptosis and differentiation assays. HE was demonstrated to inhibit the proliferation of mBMMSCs up to 45.43±3.33% and to decrease the level of PCNA expression compared with untreated cells. HE also induced late apoptosis at 24 and 48 h after treatment up to 71.93 and 67.03%, respectively, while only 14.93% of untreated cells exhibited apoptosis. By contrast, HE induced differentiation of mBMMSCs into an osteogenic lineage at the beginning of three weeks after commencement of treatment. This suggested that HE is a candidate as an inducer of osteogenesis from bone marrow mesenchymal stem cells, and additionally has potential for use in the treatment of bone metabolic disorders such as osteoporosis.

The normal cells derived from human embryonic stem cells (hESCs) are regarded as substitutes for damaged or dysfunctional adult cells. However, tumorigenicity of hESCs remains a major challenge in clinical application of hESC-derived cell transplantation. Previously, we generated monoclonal antibody (MAb) 57-C11 specific to the surface molecule on undifferentiated hESCs. The aim of this study is to prove whether 57-C11-positive hESCs are pluripotent and tumorigenic in immunodeficient mice.

Undifferentiated hESCs were mixed with retinoic acid (RA)-differentiated hESCs at different ratios prior to 57-C11-mediated separation. To isolate 57-C11-positive hESCs from the mixture, biotinylated 57-C11 and streptavidin-coated magnetic beads were added to the mixture. Unbound 57-C11-negative hESCs were first isolated after applying magnet to the cell mixture, and 57-C11-bound hESCs were then released from the magnetic beads. In order to measure the efficiency of separation, 57-C11-positive or -negative hESCs were counted after isolation. To evaluate the efficiency of teratoma formation in vivo, 57-C11-positive or negative cells were further injected into left and right, respectively, testes of nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice.

Approximately 77~100% of undifferentiated hESCs were isolated after applying 57-C11-coated magnetic beads to the mixed cell populations. Importantly, teratomas were not observed in NOD/SCID mice after the injection of isolated 57-C11-negative hESCs, whereas teratomas were observed with 57-C11-positive hESCs.

57-C11-positive hESCs are pluripotent and tumorigenic. The combination of 57-C11 and magnetic beads will be useful to eliminate remaining undifferentiated hESCs for the safe cell transplantation.

• 57-C11
• Human embryonic stem cells
• Magnetic beads
• Surface marker
• Teratoma

• Adult Stem Cells/cytology
• Adult Stem Cells/physiology
• Cell Differentiation/physiology
• Cells, Cultured
• Female
• Humans
• Male
• Reproduction/physiology
• Stem Cells/cytology
• Stem Cells/physiology

• Animals
• Cell Differentiation
• Cell- and Tissue-Based Therapy/methods
• Humans
• Retinal Degeneration/therapy
• Retinal Ganglion Cells/cytology
• Signal Transduction
• Stem Cell Transplantation
• Stem Cells/cytology

• Apoptosis
• Embryonic stem cells
• Epithelial-to-mesenchymal transition
• Induced pluripotent stem cells
• Motility
• Self-renewal

• Immunogenicity
• Safety
• Tumorigenicity

Mesenchymal stem cells (MSCs) are being assessed for ameliorating the severity of graft‐versus‐host disease, autoimmune conditions, musculoskeletal injuries and cardiovascular diseases. While most of these clinical therapeutic applications require substantial cell quantities, the number of MSCs that can be obtained initially from a single donor remains limited. The utility of MSCs derived from human‐induced pluripotent stem cells (hiPSCs) has been shown in recent pre‐clinical studies. Since adult MSCs have limited capability regarding proliferation, the quantum of bioactive factor secretion and immunomodulation ability may be constrained. Hence, the alternate source of MSCs is being considered to replace the commonly used adult tissue‐derived MSCs. The MSCs have been obtained from various adult and foetal tissues. The hiPSC‐derived MSCs (iMSCs) are transpiring as an attractive source of MSCs because during reprogramming process, cells undergo rejuvination, exhibiting better cellular vitality such as survival, proliferation and differentiations potentials. The autologous iMSCs could be considered as an inexhaustible source of MSCs that could be used to meet the unmet clinical needs. Human‐induced PSC‐derived MSCs are reported to be superior when compared to the adult MSCs regarding cell proliferation, immunomodulation, cytokines profiles, microenvironment modulating exosomes and bioactive paracrine factors secretion. Strategies such as derivation and propagation of iMSCs in chemically defined culture conditions and use of footprint‐free safer reprogramming strategies have contributed towards the development of clinically relevant cell types. In this review, the role of iPSC‐derived mesenchymal stromal cells (iMSCs) as an alternate source of therapeutically active MSCs has been described. Additionally, we also describe the role of iMSCs in regenerative medical applications, the necessary strategies, and the regulatory policies that have to be enforced to render iMSC's effectiveness in translational medicine.

• MSCs
• hiPSCs
• iMSCs
• induced pluripotent stem cells
• mesenchymal stem cells

Traumatic brain injury is a major health problem worldwide. Currently, there is no effective treatment to improve neural structural repair and functional recovery of patients in the clinic. Cell transplantation is a potential strategy to repair and regenerate the injured brain. This review article summarized recent development in cell transplantation studies for post-traumatic brain injury brain repair with varying types of cell sources. It also discussed the potential of neural transplantation to repair/promote recovery of the injured brain following traumatic brain injury.

• functional recovery
• neural transplantation
• regeneration
• stem cells
• traumatic brain injury

Tendon injuries are a common cause of physical disability. They present a clinical challenge to orthopedic surgeons because injured tendons respond poorly to current treatments without tissue regeneration and the time required for rehabilitation is long. New treatment options are required. Stem cell-based therapies offer great potential to promote tendon regeneration due to their high proliferative, synthetic, and immunomodulatory activities as well as their potential to differentiate to the target cell types and undergo genetic modification. In this review, I first recapped the challenges of tendon repair by reviewing the anatomy of tendon. Next, I discussed the advantages and limitations of using different types of stem cells compared to terminally differentiated cells for tendon tissue engineering. The safety and efficacy of application of stem cells and their modified counterparts for tendon tissue engineering were then summarized after a systematic literature search in PubMed. The challenges and future research directions to enhance, optimize, and standardize stem cell-based therapies for augmenting tendon repair were then discussed.

• stem cells
• tendon injuries
• tendon repair
• tendon tissue engineering

• Cell sheet
• Fibroblast
• Hepatocyte transplantation
• Human primary hepatocyte
• Tissue engineering
• Vascularization

In orthopedics, tissue engineering approach using stem cells is a valid line of treatment for patients with bone defects. In this context, mesenchymal stromal cells of various origins have been extensively studied and continue to be a matter of debate. Although mesenchymal stromal cells from bone marrow are already clinically applied, recent evidence suggests that one may use mesenchymal stromal cells from extra-embryonic tissues, such as amniotic fluid, as an innovative and advantageous resource for bone regeneration. The use of cells from amniotic fluid does not raise ethical problems and provides a sufficient number of cells without invasive procedures. Furthermore, they do not develop into teratomas when transplanted, a consequence observed with pluripotent stem cells. In addition, their multipotent differentiation ability, low immunogenicity, and anti-inflammatory properties make them ideal candidates for bone regenerative medicine. We here present an overview of the features of amniotic fluid mesenchymal stromal cells and their potential in the osteogenic differentiation process. We have examined the papers actually available on this regard, with particular interest in the strategies applied to improve in vitro osteogenesis. Importantly, a detailed understanding of the behavior of amniotic fluid mesenchymal stromal cells and their osteogenic ability is desirable considering a feasible application in bone regenerative medicine.

• Mesenchymal stromal cells
• Amniotic fluid
• Amniotic fluid mesenchymal stromal cells
• Amniotic fluid stem cells
• Osteogenesis
• Bone regeneration

• Cell Differentiation
• Cell Separation/instrumentation
• Cell Separation/methods
• Electrophoresis
• Equipment Design
• Humans
• Mesenchymal Stem Cells/cytology
• Microfluidic Analytical Techniques/instrumentation
• Microfluidic Analytical Techniques/methods
• Osteoblasts/cytology

• ZIA BC005093 Intramural NIH HHS

• embryonic stem cells
• human
• feeder layers
• 3-d culture
• hydrogel
• cell adhesion
• ecm (extracellular matrix)
• tissue regeneration
• differentiation
• pluripotent

• Animals
• Cell Culture Techniques/history
• Cell Culture Techniques/trends
• Cell Proliferation
• Coculture Techniques
• Culture Media
• Feeder Cells
• History, 20th Century
• History, 21st Century
• Human Embryonic Stem Cells
• Humans
• Mice
• Stem Cell Research/history