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.

Biochemical basis for pharmacological intervention as a reprogramming strategy against hypertension and kidney disease of developmental origin.

The concept of "developmental origins of health and disease" (DOHaD) stipulates that both hypertension and kidney disease may take origin from early-life insults. The DOHaD concept also offers reprogramming strategies aiming at shifting therapeutic interventions from adulthood to early life, even before clinical symptoms are evident. Based on those two concepts, this review will present the evidence for the existence of, and the programming mechanisms in, kidney developmental programming that may lead to hypertension and kidney disease. This will be followed by potential pharmacological interventions that may serve as a reprogramming strategy to counter the rising epidemic of hypertension and kidney disease. We point out that before patients could benefit from this strategy, the most pressing issue is for the growing body of evidence from animal studies in support of pharmacological intervention as a reprogramming strategy to long-term protect against hypertension and kidney disease of developmental origins to be validated clinically and the critical window, drug dose, dosing regimen, and therapeutic duration identified.

Gene and Cell Therapy for ß-Thalassemia and Sickle Cell Disease with Induced Pluripotent Stem Cells (iPSCs): The Next Frontier.

In recent years, breakthroughs in human pluripotent stem cell (hPSC) research, namely cellular reprogramming and the emergence of sophisticated genetic engineering technologies, have opened new frontiers for cell and gene therapy. The prospect of using hPSCs, either autologous or histocompatible, as targets of genetic modification and their differentiated progeny as cell products for transplantation, presents a new paradigm of regenerative medicine of potential tremendous value for the treatment of blood disorders, including beta-thalassemia (BT) and sickle cell disease (SCD). Despite advances at a remarkable pace and great promise, many roadblocks remain before clinical translation can be realistically considered. Here we discuss the theoretical advantages of cell therapies utilizing hPSC derivatives, recent proof-of-principle studies and the main challenges towards realizing the potential of hPSC therapies in the clinic.

Direct Reprogramming, Epigenetics, and Cardiac Regeneration.

The discovery of induced pluripotent stem cells (iPSCs) has revolutionized regenerative medicine. Autologous iPSCs can be generated by introducing 4 stem cell-specific factors (Oct4, Sox2, Klf4, c-Myc) into fibroblasts. iPSCs can propagate indefinitely and differentiate into clinically important cell types, including cardiomyocytes, in vitro. The iPSC-derived cardiomyocytes represent a promising source of cells for cell-based therapeutic approaches for cardiac regeneration. However, there are several challenges in the clinical application of iPSCs: tumorigenicity of immature cells, poor survival of the transplanted myocardial cells, and cost and efficacy of this therapeutic approach. We developed a new alternate approach for cardiac regeneration, called direct cardiac reprogramming. Instead of using stem cell factors, we overexpressed combinations of cardiac cell-specific genes in fibroblasts to directly induce cardiomyocytes without mediating through iPSCs. The direct reprogramming approach may overcome the challenges faced in the applicability of iPSC-based cell therapy. After the development of direct cardiac reprogramming, great progress has been made in improving the efficiency of direct cardiac reprogramming and applying this technology to regenerative medicine. Here, we provide an overview of the recent progress made, epigenetics, and potential clinical applications of direct cardiac reprogramming.

Biomaterials for Abrogating Metastasis: Bridging the Gap between Basic and Translational Research.

Herein lies the issue of how to best approach cancer metastasis therapeutics in a focused, directed and efficacious manner. The lack of standardized means to efficiently deliver therapeutic cargo to metastatic sites calls for a paradigm shift in the way we view and treat metastasis. It is crucial to leverage the potential of nanomedicine to differentially combat cancer spread at each stage of the disease (primary tumor growth and formation of metastases) while considering the optimal administration route. We propose to implement three possible strategies to treat cancer as a function of disease type and state, while leveraging the advancement in materials design and in particular nanotechnology: (1) local primary tumor abrogation; (2) primary tumor re-programming to prevent metastasis; and (3) combination (local and systemic) therapy when metastasis has already transpired. Herein, we highlight potential means to bridge the gap between basic and translational research as related to metastasis therapy.

iPSCs-based anti-aging therapies: Recent discoveries and future challenges.

The main biological hallmarks of the aging process include stem cell exhaustion and cellular senescence. Consequently, research efforts to treat age-related diseases as well as anti-aging therapies in general have recently focused on potential 'reprogramming' regenerative therapies. These new approaches are based on induced pluripotent stem cells (iPSCs), including potential in vivo reprogramming for tissue repair. Another possibility is targeting pathways of cellular senescence, e.g., through modulation of p16INK4a signaling and especially inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Here, we reviewed and discussed these recent developments together with their possible usefulness for future treatments against sarcopenia, a major age-related condition.

Lineage Reprogramming: A Promising Road for Pancreatic ß Cell Regeneration.

Cell replacement therapy is a promising method to restore pancreatic ß cell function and cure diabetes. Distantly related cells (fibroblasts, keratinocytes, and muscle cells) and developmentally related cells (hepatocytes, gastrointestinal, and pancreatic exocrine cells) have been successfully reprogrammed into ß cells in vitro and in vivo. However, while some reprogrammed ß cells bear similarities to bona fide ß cells, others do not develop into fully functional ß cells. Here we review various strategies currently used for ß cell reprogramming, including ectopic expression of specific transcription factors associated with islet development, repression of maintenance factors of host cells, regulation of epigenetic modifications, and microenvironmental changes. Development of simple and efficient reprogramming methods is a key priority for developing fully functional ß cells suitable for cell replacement therapy.

The Human Endocrine Pancreas: New Insights on Replacement and Regeneration.

Islet transplantation is an effective cell therapy for type 1 diabetes (T1D) but its clinical application is limited due to shortage of donors. After a decade-long period of exploration of potential alternative cell sources, the field has only recently zeroed in on two of them as the most likely to replace islets. These are pluripotent stem cells (PSCs) (through directed differentiation) and pancreatic non-endocrine cells (through directed differentiation or reprogramming). Here we review progress in both areas, including the initiation of Phase I/II clinical trials using human embryonic stem cell (hESc)-derived progenitors, advances in hESc differentiation in vitro, novel insights on the developmental plasticity of the pancreas, and groundbreaking new approaches to induce ß cell conversion from the non-endocrine compartment without genetic manipulation.

Regenerative Medicine: Solution in Sight.

The retina, like other central nervous system tissues, has poor regenerative properties in humans. Therefore, diseases that cause retinal cell loss, such as Age-related macular degeneration (AMD), retinitis pigmentosa (RP), Leber congenital amaurosis, Usher syndrome, glaucoma, and diabetic retinopathy, typically result in permanent visual impairment. Stem cell technologies have revolutionized our ability to produce neural cells in abundant supply. Much stem cell research effort is focused on producing the required cell types for cell replacement, or to generate disease-in-a-dish models to elucidate novel disease mechanisms for therapeutic development. Here we review the recent advances in stem cell studies relevant to producing RPE and retinal cells, and highlight future directions.

Transdifferentiation via transcription factors or microRNAs: Current status and perspective.

Transdifferentiation as a new approach for obtaining the ideal cells for transplantation has gradually become a hot research topic. Compared with the induced pluripotent stem cells technique, transdifferentiation may have better efficiency and safety. Although the mechanism of transdifferentiation is still unknown, many studies have achieved transformation of one cell type to another through transcription factors or microRNA. The current major strategy for transdifferentiation is via transcription factors; however, there are some safety issues with the use of transcription factors. In contrast, microRNA as a novel tool for inducing transdifferentiation through post-transcriptional regulation may be more safe and efficient. In addition, the present transdifferentiation strategies involve obtaining the terminal cell directly, so the amount of cells produced may not be sufficient and they may have low capacity for cell immigration and integration. Therefore, an indirect transdifferentiation strategy for producing unipotent cells is ideal as it can preserve the proliferation capacity and differentiation pathway.

[New immunotherapeutic approaches in oncology and hematology]. / Nouvelles approches d'immunothérapie en onco-hématologie.

Scientific advances in the last decade have demonstrated the critical role of host immune system in the elimination and suppression of cancer cells. Better knowledge of signaling pathways has enabled the development of new cancer immunotherapy. The discovery of negative feedback mechanisms following the lymphocyte activation has promoted the development of new antibodies targeting molecule inhibitors such as PD1, PDL1 or CTLA-4. Dramatic results were obtained with melanoma. Checkpoint inhibitors (pembrolizumab and ipilimumab) have many advantages in terms of rate of objective response and overall survival. Recent studies in translational research aimed to understand and analyze mechanisms of action of anti-PD1/anti-PDL1. Expression of PDL1 in the tumor is associated with a significantly greater objective response rate (immunohistochemistry). Nevertheless, limits with tumor immunohistochemical analysis encourage new biomarkers research. Other immunotherapy approaches, such as cell and gene therapies using engineered T cells call for further advancements to broaden their applicability. However, these therapies are very expensive and their manufacturing process very restrictive, which could lately limit their use in case of inefficiency of checkpoint inhibitors or when lymphocytic infiltration in tumor is absent. In this case, the objective would be to engineer ex vivo the patient's immune system by restoring the ability of T cells to identify and suppress tumor cells. Currently, two gene-reprogramming tools are under development: chimeric antigen receptor and TCR modified T cells.

[Pluripotent stem cells as a source for T cell research and clinical application].

Recently, promising clinical outcomes of cancer immunotherapy including administration of an anti PD-1 antibody targeting for T cell reactivation has gained particular attention worldwide. Adoptive cell therapy with tumor infiltrating lymphocytes and TCR/CAR (Chimeric Antigen Receptor) transgenic T cells are also under development. Although it has become clearer that the efficacy of adoptive cell therapy correlate with the quality of infusing T cells, antigen specific T cells in patients with chronic infection and cancer have been exhausted. We have succeeded to generate rejuvenated antigen specific T cells by reprogramming to pluripotency and differentiation. In this article, we introduce fundamentals of this technology and describe its potential for adoptive cell therapy in the future.