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Induced pluripotent stem cell technology: a decade of progress
Key Points
Human induced pluripotent stem cell (iPSC) technology has evolved rapidly since its inception in 2007.
Human iPSC technology has been widely used for disease modelling; for example, for neurodegenerative and psychiatric disorders.
Human iPSC technology has yielded several drug candidates that are currently in clinical trials.
The first clinical trial using human iPSC-derived products has been initiated for age-related macular degeneration.
The combination with gene editing and 3D organoid technologies makes the iPSC platform more powerful.
The continued development of iPSC technology and its integration with other technologies has the potential to make substantial contributions to disease modelling, drug discovery and regenerative medicine.
Since the advent of induced pluripotent stem cell (iPSC) technology a decade ago, human iPSCs have been widely used for disease modelling, drug discovery and cell therapy development. This article discusses progress in applications of iPSC technology that are particularly relevant to drug discovery and regenerative medicine, including the powerful combination of human iPSC technology with recent developments in gene editing.
Since the advent of induced pluripotent stem cell (iPSC) technology a decade ago, enormous progress has been made in stem cell biology and regenerative medicine. Human iPSCs have been widely used for disease modelling, drug discovery and cell therapy development. Novel pathological mechanisms have been elucidated, new drugs originating from iPSC screens are in the pipeline and the first clinical trial using human iPSC-derived products has been initiated. In particular, the combination of human iPSC technology with recent developments in gene editing and 3D organoids makes iPSC-based platforms even more powerful in each area of their application, including precision medicine. In this Review, we discuss the progress in applications of iPSC technology that are particularly relevant to drug discovery and regenerative medicine, and consider the remaining challenges and the emerging opportunities in the field.
Journal Article
Dynamic regulation of human endogenous retroviruses mediates factor-induced reprogramming and differentiation potential
Pluripotency can be induced in somatic cells by overexpressing transcription factors, including POU class 5 homeobox 1 (OCT3/4), sex determining region Y-box 2 (SOX2), Krüppel-like factor 4 (KLF4), and myelocytomatosis oncogene (c-MYC). However, some induced pluripotent stem cells (iPSCs) exhibit defective differentiation and inappropriate maintenance of pluripotency features. Here we show that dynamic regulation of human endogenous retroviruses (HERVs) is important in the reprogramming process toward iPSCs, and in re-establishment of differentiation potential. During reprogramming, OCT3/4, SOX2, and KLF4 transiently hyperactivated LTR7s—the long-terminal repeats of HERV type-H (HERV-H)—to levels much higher than in embryonic stem cells by direct occupation of LTR7 sites genome-wide. Knocking down LTR7s or long intergenic non-protein coding RNA, regulator of reprogramming (lincRNA-RoR), a HERV-H–driven long noncoding RNA, early in reprogramming markedly reduced the efficiency of iPSC generation. KLF4 and LTR7 expression decreased to levels comparable with embryonic stem cells once reprogramming was complete, but failure to resuppress KLF4 and LTR7s resulted in defective differentiation. We also observed defective differentiation and LTR7 activation when iPSCs had forced expression of KLF4. However, when aberrantly expressed KLF4 or LTR7s were suppressed in defective iPSCs, normal differentiation was restored. Thus, a major mechanism by which OCT3/4, SOX2, and KLF4 promote human iPSC generation and reestablish potential for differentiation is by dynamically regulating HERV-H LTR7s.
Journal Article
Dreams and due diligence : Till and McCulloch's stem cell discovery and legacy
\"In proving the existence of stem cells, Ernest Armstrong McCulloch and James Edgar Till formed the most important partnership in Canadian medical research since Frederick Banting and Charles Best, the discoverers of insulin. Together, Till and McCulloch instructed, influenced, and inspired successive generations of researchers who have used their findings to make huge advances against disease. Thousands of people who would have died from leukemia and immunological disorders now owe their lives to therapies supported by their seminal discoveries\"-- Dust jacket flap.
Book
Mesenchymal and haematopoietic stem cells form a unique bone marrow niche
The cellular constituents forming the haematopoietic stem cell (HSC) niche in the bone marrow are unclear, with studies implicating osteoblasts, endothelial and perivascular cells. Here we demonstrate that mesenchymal stem cells (MSCs), identified using nestin expression, constitute an essential HSC niche component. Nestin
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MSCs contain all the bone-marrow colony-forming-unit fibroblastic activity and can be propagated as non-adherent ‘mesenspheres’ that can self-renew and expand in serial transplantations. Nestin
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MSCs are spatially associated with HSCs and adrenergic nerve fibres, and highly express HSC maintenance genes. These genes, and others triggering osteoblastic differentiation, are selectively downregulated during enforced HSC mobilization or β3 adrenoreceptor activation. Whereas parathormone administration doubles the number of bone marrow nestin
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cells and favours their osteoblastic differentiation,
in vivo
nestin
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cell depletion rapidly reduces HSC content in the bone marrow. Purified HSCs home near nestin
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MSCs in the bone marrow of lethally irradiated mice, whereas
in vivo
nestin
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cell depletion significantly reduces bone marrow homing of haematopoietic progenitors. These results uncover an unprecedented partnership between two distinct somatic stem-cell types and are indicative of a unique niche in the bone marrow made of heterotypic stem-cell pairs.
A stem-cell niche made for two
The identity of the cells that form the haematopoietic stem-cell niche in the bone marrow has been unclear. Paul Frenette and colleagues have now identified nestin-expressing mesenchymal stem cells as niche-forming cells. These cells show a close physical association with haematopoietic stem cells, express high levels of genes involved in stem-cell maintenance, and their depletion reduces bone-marrow homing of haematopoietic progenitors. This work reveals the stem-cell niche in the bone marrow as a partnership between two distinct somatic stem-cell types.
The identity of the cells that form the haematopoietic stem cell (HSC) niche in bone marrow has been unclear. These authors identify nestin-expressing mesenchymal stem cells as niche-forming cells. These nestin-expressing cells show a close physical association with HSCs and express high levels of genes involved in HSC maintenance, and their depletion reduces bone marrow homing of haematopoietic progenitors.
Journal Article
Embryonic Stem Cell‐Derived Mesenchymal Stem Cells (MSCs) Have a Superior Neuroprotective Capacity Over Fetal MSCs in the Hypoxic‐Ischemic Mouse Brain
Human mesenchymal stem cells (MSCs) have huge potential for regenerative medicine. In particular, the use of pluripotent stem cell‐derived mesenchymal stem cells (PSC‐MSCs) overcomes the hurdle of replicative senescence associated with the in vitro expansion of primary cells and has increased therapeutic benefits in comparison to the use of various adult sources of MSCs in a wide range of animal disease models. On the other hand, fetal MSCs exhibit faster growth kinetics and possess longer telomeres and a wider differentiation potential than adult MSCs. Here, for the first time, we compare the therapeutic potential of PSC‐MSCs (ES‐MSCs from embryonic stem cells) to fetal MSCs (AF‐MSCs from the amniotic fluid), demonstrating that ES‐MSCs have a superior neuroprotective potential over AF‐MSCs in the mouse brain following hypoxia‐ischemia. Further, we demonstrate that nuclear factor (NF)‐κB‐stimulated interleukin (IL)‐13 production contributes to an increased in vitro anti‐inflammatory potential of ES‐MSC‐conditioned medium (CM) over AF‐MSC‐CM, thus suggesting a potential mechanism for this observation. Moreover, we show that induced pluripotent stem cell‐derived MSCs (iMSCs) exhibit many similarities to ES‐MSCs, including enhanced NF‐κB signaling and IL‐13 production in comparison to AF‐MSCs. Future studies should assess whether iMSCs also exhibit similar neuroprotective potential to ES‐MSCs, thus presenting a potential strategy to overcome the ethical issues associated with the use of embryonic stem cells and providing a potential source of cells for autologous use against neonatal hypoxic‐ischemic encephalopathy in humans. Stem Cells Translational Medicine 2018;7:439–449 We hypothesize that the increased nuclear factor (NF)‐κB activation and, therefore, higher levels of interleukin (IL)‐13 production observed in pluripotent stem cell‐derived mesenchymal stem cells contributes to the increased anti‐inflammatory potential of these cells compared with other types of mesenchymal stem cells.
Journal Article
Intra‐Articular Injection of Autologous Adipose Tissue‐Derived Mesenchymal Stem Cells for the Treatment of Knee Osteoarthritis: A Phase IIb, Randomized, Placebo‐Controlled Clinical Trial
Mesenchymal stem cells (MSCs) have been the focus of an emerging treatment for osteoarthritis. However, few studies reported about outcomes of an intra‐articular injection of autologous adipose‐derived mesenchymal stem cells (AD‐MSCs). This study aimed to assess the efficacy and safety of a single intra‐articular injection of AD‐MSCs for patients with knee osteoarthritis. It was a prospective double‐blinded, randomized controlled, phase IIb clinical trial. AD‐MSCs were administered for 12 patients (MSC group), and the group was compared with 12 knees with injection of normal saline (control group) up to 6 months. All procedures were performed in the outpatient clinic. Primary outcome measure was the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) score. Secondary outcome measure included various clinical and radiologic examination, and safety after injection. Change of cartilage defect after injection was evaluated using magnetic resonance imaging (MRI). Single injection of AD‐MSCs led to a significant improvement of the WOMAC score at 6 months. In the control group, there was no significant change in the WOMAC score at 6 months. No serious adverse events were observed in both groups during the follow‐up period. In MRI, there was no significant change of cartilage defect at 6 months in MSC group whereas the defect in the control group was increased. An intra‐articular injection of autologous AD‐MSCs provided satisfactory functional improvement and pain relief for patients with knee osteoarthritis in the outpatient setting, without causing adverse events at 6 months' follow‐up. Larger sample size and long‐term follow‐up are required. Stem Cells Translational Medicine 2019;8:504–511 Autologous adipose‐derived mesenchymal stem cells (AD‐MSCs) were administered for 12 patients, and the group was compared with 12 knees with injection of normal saline up to 6 months. The procedures were performed in an outpatient clinic. An intra‐articular injection of autologous AD‐MSCs provided satisfactory functional improvement and pain relief in patients with knee osteoarthritis without causing adverse events at 6 months' follow‐up.
Journal Article
Feasibility of reduced-dose posttransplant cyclophosphamide and cotransplantation of peripheral blood stem cells and umbilical cord-derived mesenchymal stem cells for SAA
Posttransplant cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis is an effective strategie for patients receiving matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) and haploidentical HSCT (haplo-HSCT). We evaluated the effectiveness and safety of reduced-dose cyclophosphamide, 20 mg/kg for 13 patients in MSD-HSCT cohort and 25 mg/kg for 22 patients in haplo-HSCT cohort, on days + 3, + 4 combined with cotransplantation of peripheral blood stem cells (PBSCs) and human umbilical cord-derived mesenchymal stem cells (UC-MSCs) for severe aplastic anemia (SAA). In MSD-PTCy cohort, the times to neutrophil and platelet engraftment were significantly shorter than those in the MSD-control cohort (P < 0.05). The cumulative incidence of acute GVHD (aGVHD) at day + 100 (15.4%) was lower than that in the MSD-control cohort (P = 0.050). No patient developed chronic GVHD (cGVHD). The 1-year overall survival (OS) and event-free survival (EFS) rates were 100% and 92.3%. In haplo-PTCy cohort, the times to neutrophil and platelet engraftment were significantly shorter than those in the haplo-control cohort (P < 0.05). The cumulative incidences of aGVHD at day + 100 and 1-year cGVHD were 31.8% and 18.2%, and the 1-year OS and EFS rates were 81.8% and 66.9%. Reduced-dose PTCy and cotransplantation of PBSCs and UC-MSCs is an acceptable alternative to patients with SAA.
Journal Article
Stem cells: past, present, and future
In recent years, stem cell therapy has become a very promising and advanced scientific research topic. The development of treatment methods has evoked great expectations. This paper is a review focused on the discovery of different stem cells and the potential therapies based on these cells. The genesis of stem cells is followed by laboratory steps of controlled stem cell culturing and derivation. Quality control and teratoma formation assays are important procedures in assessing the properties of the stem cells tested. Derivation methods and the utilization of culturing media are crucial to set proper environmental conditions for controlled differentiation. Among many types of stem tissue applications, the use of graphene scaffolds and the potential of extracellular vesicle-based therapies require attention due to their versatility. The review is summarized by challenges that stem cell therapy must overcome to be accepted worldwide. A wide variety of possibilities makes this cutting edge therapy a turning point in modern medicine, providing hope for untreatable diseases.
Journal Article