Perinatal stem cells: A promising cell resource for tissue engineering of craniofacial bone

In facing the mounting clinical challenge and suboptimal techniques of craniofacial bone defects resulting from various conditions, such as congenital malformations, osteomyelitis, trauma and tumor resection, the ongoing research of regenerative medicine using stem cells and concurrent advancement in biotechnology have shifted the focus from surgical reconstruction to a novel stem cell-based tissue engineering strategy for customized and functional craniofacial bone regeneration. Given the unique ontogenetical and cell biological properties of perinatal stem cells, emerging evidence has suggested these extraembryonic tissue-derived stem cells to be a promising cell source for extensive use in regenerative medicine and tissue engineering. In this review, we summarize the current achievements and obstacles in stem cell-based craniofacial bone regeneration and subsequently we address the characteristics of various types of perinatal stem cells and their novel application in tissue engineering of craniofacial bone. We propose the promising feasibility and scope of perinatal stem cell-based craniofacial bone tissue engineering for future clinical application.     

Straight talk with... Mahendra Rao by Dolgin Elie

In October 2005, Mahendra Rao shocked the scientific community when he quit his job as head of the US National Institute on Aging's stem cell section and announced plans to go into industry. Rao felt that a ban at the time on federal funding for most human embryonic stem cell research hampered researchers in his division and prohibited him from doing the job he was hired to do. So he joined the research-tool giant Invitrogen (which later became Life Technologies) as vice president of regenerative medicine at the company's Maryland facility. Six years on, times have changed in the field of stem cell biology: rules governing taxpayer-backed research involving embryonic stem (ES) cells have been relaxed in the US, and induced pluripotent stem (iPS) cells have come into the fray. Prompted by those changes, Rao opted to return to the US National Institutes of Health (NIH) in August to head the new Intramural Center for Regenerative Medicine. The $52 million center was launched in early 2010 by the agency to develop new therapies using stem cell approaches. With a heightened focus at the NIH on translational medicine, Elie Dolgin spoke to Rao to find out how he plans to turn stem cell discoveries into cell-based therapies.     

Recent trends in stem cell-based therapies and applications of artificial intelligence in regenerative medicine

Stem cells are undifferentiated cells that can self-renew and differentiate into diverse types of mature and functional cells while maintaining their original identity. This profound potential of stem cells has been thoroughly investigated for its significance in regenerative medicine and has laid the foundation for cell-based therapies. Regenerative medicine is rapidly progressing in healthcare with the prospect of repair and restoration of specific organs or tissue injuries or chronic disease conditions where the body’s regenerative process is not sufficient to heal. In this review, the recent advances in stem cell-based therapies in regenerative medicine are discussed, emphasizing mesenchymal stem cell-based therapies as these cells have been extensively studied for clinical use. Recent applications of artificial intelligence algorithms in stem cell-based therapies, their limitation, and future prospects are highlighted.     

Developments in clinical cell therapy

Immunotherapy has become an important part of hematopoietic stem cell (HSC) transplantation and cancer therapy. Regenerative and reparative properties of somatic cell-based therapies hold tremendous promise for repairing injured tissue, preventing and reversing damage to organs, and restoring balance to compromised immune systems. The principles and practices of the diverse aspects of immune therapy for cancer, HSC transplantation and regenerative medicine have many commonalities. This meeting report summarizes a workshop sponsored by the National Heart, Lung and Blood Institute (NHLBI) and Production Assistance for Cellular Therapies (PACT), held on 23–24 April 2009 at the National Institutes of Health (NIH, USA). A series of scientific sessions and speakers highlighted key aspects of the latest scientific, clinical and technologic developments in cell therapy, involving a unique set of cell products with a special emphasis on converging concepts in these fields.     

Prion diseases and adult neurogenesis: How do prions counteract the brain's endogenous repair machinery?

Scientific advances in stem cell biology and adult neurogenesis have raised the hope that neurodegenerative disorders could benefit from stem cell-based therapy.Adult neurogenesis might be part of the physiological regenerative process; however, it might become impaired by the disease''s mechanism and therefore contribute to neurodegeneration. In prion disorders this endogenous repair system has rarely been studied. Whether adult neurogenesis plays a role or not in brain repair or in the propagation of prion pathology remains unclear. We have recently investigated the status of adult neural stem cells isolated from prion-infected mice. We were able to show that neural stem cells accumulate and replicate prions thus resulting in an alteration of their neuronal destiny. We also reproduced these results in adult neural stem cells, which were infected in vitro. The fact that endogenous adult neurogenesis could be altered by the accumulation of misfolded prion protein represents another great challenge. Inhibiting prion propagation in these cells would thus help the endogenous neurogenesis to compensate for the injured neuronal system. Moreover, understanding the endogenous modulation of the neurogenesis system would help develop effective neural stem cell-based therapies.     

NHLBI plans for the promise of cell-based therapies

This article presents the National Heart, Lung and Blood Institute (NHLBI) perspective on the status of cell-based therapies. A summary of current and future NHLBI/National Institutes of Health (NIH) programs is given along with a history of the development of NHLBI/NIH resources to aid the advancement of cell-based therapies. A brief discussion of clinical research programs to utilize cell-based therapies is also included.     

Adipose-derived stromal cell in regenerative medicine: A review

The application of appropriate cell origin for utilizing inregenerative medicine is the major issue. Various kinds of stem cells have been used for the tissue engineering and regenerative medicine. Such as, several stromal cells have been employed as treat option for regenerative medicine. For example, human bone marrow-derived stromal cells and adipose-derived stromal cells(ADSCs) are used in cell-based therapy. Data relating to the stem cell therapy and processes associated with ADSC has developed remarkably in the past 10 years. As medical options, both the stromal vascular and ADSC suggests good opportunity as marvelous cell-based therapeutics. The some biological features are the main factors that impact the regenerative activity of ADSCs, including the modulation of the cellular immune system properties and secretion of bioactive proteins such as cytokines, chemokines and growth factors, as well as their intrinsic anti-ulcer and anti-inflammatory potential. A variety of diseases have been treated by ADSCs, and it is not surprising that there has been great interest in the possibility that ADSCs might be used as therapeutic strategy to improve a wider range of diseases. This is especially important when it is remembered that routine therapeutic methods are not completely effective in treat of diseases. Here, it was discuss about applications of ADSC to colitis, liver failure, diabetes mellitus, multiple sclerosis, orthopaedic disorders, hair loss, fertility problems, and salivary gland damage.     

Induced Pluripotency for Translational Research

The advent of induced pluripotent stem cells （iPSCs） has revolutionized the concept of cellular reprogramming and potentially will solve the immunological compatibility issues that have so far hindered the application of human pluripotent stem cells in regenerative medicine. Recent findings showed that pluripotency is defined by a state of balanced lineage potency, which can be artificially instated through various procedures, including the conventional Yamanaka strategy. As a type of pluripotent stem cell, iPSCs are subject to the usual concerns over purity of differen- tiated derivatives and risks of tumor formation when used for cell-based therapy, though they pro- vide certain advantages in translational research, especially in the areas of personalized medicine, disease modeling and drug screening, iPSC-based technology, human embryonic stem cells （hESCs） and direct lineage conversion each will play distinct roles in specific aspects of translational medi- cine, and continue yielding surprises for scientists and the public.     

干细胞临床应用现状及管理对策

干细胞研究及以其为基础的再生医学技术已经成为生物医学发展水平的重要标志之一。对于大量组织器官缺损或功能障碍患者构成的巨大医疗市场来说,干细胞与再生医学的研究与开发将产生重要影响,其进程也日益加快。干细胞根据来源和获得方式可分为胚胎干细胞、重编程干细胞及成体干细胞等类型,不同类型干细胞特点不同,技术成熟程度处于不同发展阶段,在可能的使用过程中风险规避的策略不同,不同来源的干细胞产品针对的临床适应症和准入标准也不尽相同。在概述这三类干细胞基础研究的基础上,对应用现状和发展趋势进行述评,并提出相关的管理策略。     

Shaping the eye from embryonic stem cells: Biological and medical implications

Organogenesis is regulated by a complex network of intrinsic cues, diffusible signals and cell/cell or cell/matrix interactions that drive the cells of a prospective organ to differentiate and collectively organize in three dimensions. Generating organs in vitro from embryonic stem (ES) cells may provide a simplified system to decipher how these processes are orchestrated in time and space within particular and between neighboring tissues. Recently, this field of stem cell research has also gained considerable interest for its potential applications in regenerative medicine. Among human pathologies for which stem cell-based therapy is foreseen as a promising therapeutic strategy are many retinal degenerative diseases, like retinitis pigmentosa and age-related macular degeneration. Over the last decade, progress has been made in producing ES-derived retinal cells in vitro, but engineering entire synthetic retinas was considered beyond reach. Recently however, major breakthroughs have been achieved with pioneer works describing the extraordinary self-organization of murine and human ES cells into a three dimensional structure highly resembling a retina. ES-derived retinal cells indeed assemble to form a cohesive neuroepithelial sheet that is endowed with the intrinsic capacity to recapitulate, outside an embryonic environment, the main steps of retinal morphogenesis as observed in vivo. This represents a tremendous advance that should help resolving fundamental questions related to retinogenesis. Here, we will discuss these studies, and the potential applications of such stem cell-based systems for regenerative medicine.     

Peripheral blood mononuclear cell secretome for tissue repair

For almost two decades, cell-based therapies have been tested in modern regenerative medicine to either replace or regenerate human cells, tissues, or organs and restore normal function. Secreted paracrine factors are increasingly accepted to exert beneficial biological effects that promote tissue regeneration. These factors are called the cell secretome and include a variety of proteins, lipids, microRNAs, and extracellular vesicles, such as exosomes and microparticles. The stem cell secretome has most commonly been investigated in pre-clinical settings. However, a growing body of evidence indicates that other cell types, such as peripheral blood mononuclear cells (PBMCs), are capable of releasing significant amounts of biologically active paracrine factors that exert beneficial regenerative effects. The apoptotic PBMC secretome has been successfully used pre-clinically for the treatment of acute myocardial infarction, chronic heart failure, spinal cord injury, stroke, and wound healing. In this review we describe the benefits of choosing PBMCs instead of stem cells in regenerative medicine and characterize the factors released from apoptotic PBMCs. We also discuss pre-clinical studies with apoptotic cell-based therapies and regulatory issues that have to be considered when conducting clinical trials using cell secretome-based products. This should allow the reader to envision PBMC secretome-based therapies as alternatives to all other forms of cell-based therapies.     

Can human embryonic stem cells contribute to the discovery of safer and more effective drugs?

Few scientific achievements have received such irresistible attention from scientists, clinicians, and the general public as the ability of human embryonic stem (hES) cells to differentiate into functional cell types for regenerative medicine. The most immediate benefit of neurons, cardiomyocytes, and insulin-secreting cells derived from hES cells, however, may reside in their application in drug discovery and toxicology. The availability of renewable human cells with functional similarities to their in vivo counterparts is the first landmark for a new generation of cell-based assays. The development of cell-based assays using human cells that are physiological targets of drug activity will increase the robustness of target validation and efficacy, high-throughput screening (HTS), structure-activity relationship (SAR), and should introduce safer drugs into clinical trials and the marketplace. The pluripotency of embryonic stem cells, that is, the capacity to generate multiple cell types, is a novel path for the discovery of 'regenerative drugs', the pursuit of small molecules that promote tissue repair (neurogenesis, cardiogenesis) or proliferation of resident stem cells in different organs, thus creating drugs that work by a novel mechanism.     

Cell-based cardiovascular repair and regeneration in acute myocardial infarction and chronic ischemic cardiomyopathy-current status and future developments

Ischemic heart disease is the main cause of death and morbidity in most industrialized countries. Stem- and progenitor cell-based treatment approaches for ischemic heart disease are therefore an important frontier in cardiovascular and regenerative medicine. Experimental studies have shown that bone-marrow-derived stem cells and endothelial progenitor cells can improve cardiac function after myocardial infarction, clinical phase I and II studies were rapidly initiated to translate this concept into the clinical setting. However, as of now the effects of stem/progenitor cell administration on cardiac function in the clinical setting have not met expectations. Thus, a better understanding of causes of the current limitations of cell-based therapies is urgently required. Importantly, the number and function of endothelial progenitor cells is reduced in patients with cardiovascular risk factors and/or coronary artery disease. These observations may provide opportunities for an optimization of cell-based treatment approaches. This review provides a summary of current evidence for the role and potential of stem and progenitor cells in the pathophysiology and treatment of ischemic heart disease, including the properties, and repair and regenerative capacities of various stem and progenitor cell populations. In addition, we describe modes of stem/progenitor cell delivery, modulation of their homing as well as potential approaches to "prime" stem/progenitor cells for cardiovascular cell-based therapies.     

Mesenchymal stem cells and skin wound repair and regeneration: possibilities and questions

Adult mesenchymal stem cells (MSCs) have the capacity for self-renewal and for differentiating into a variety of cells and tissues. They may leave their niche to migrate to remote tissues and play a critical role in wound repair and tissue regeneration. Because of their multipotency, easy isolation and culture, highly expansive potential, and immunosuppression properties, these cells may be an attractive therapeutic tool for regenerative medicine and tissue engineering. Several studies have indicated a contribution of MSCs to reconstituting skin in cutaneous wounds, but problems still need resolution before MSCs can be widely used clinically. This review focuses mainly on the benefits of MSCs in skin wound healing and tissue regeneration and on the questions that remain to be answered before MSCs can be used in clinical practice. This study was supported in part by the National Natural Science Foundation of China (30730090, 30672176, 30500194) and by State Key Development Program of Basic Research of China (973 Program, 2005CB522603).     

Clinical translation of stem cells: insight for cartilage therapies

Abstract

The limited regenerative capacity of articular cartilage and deficiencies of current treatments have motivated the investigation of new repair technologies. In vitro cartilage generation using primary cell sources is limited by cell availability and expansion potential. Pluripotent stem cells possess the capacity for chondrocytic differentiation and extended expansion, providing a potential future solution to cell-based cartilage regeneration. However, despite successes in producing cartilage using adult and embryonic stem cells, the translation of these technologies to the clinic has been severely limited. This review discusses recent advances in stem cell-based cartilage tissue engineering and the major current limitations to clinical translation of these products. Concerns regarding appropriate animal models and studies, stem cell manufacturing, and relevant regulatory processes and guidelines will be addressed. Understanding the significant hurdles limiting the clinical use of stem cell-based cartilage may guide future developments in the fields of tissue engineering and regenerative medicine.     

The emerging biology of satellite cells and their therapeutic potential

Adult skeletal muscle contains an abundant and highly accessible population of muscle stem and progenitor cells called satellite cells. The primary function of satellite cells is to mediate postnatal muscle growth and repair. Owing to their availability and remarkable capacity to regenerate damaged muscle, satellite cells and their descendent myoblasts have been considered as powerful candidates for cell-based therapies to treat muscular dystrophies and other neuromuscular diseases. However, regenerative medicine in muscle repair requires a thorough understanding of, and the ability to manipulate, the molecular mechanisms that control the proliferation, self-renewal and myogenic differentiation of satellite cells. Here, we review the latest advances in our current understanding of the quiescence, activation, proliferation and self-renewal of satellite cells and the challenges in the development of satellite cell-based regenerative medicine.     

Strategies to improve regenerative potential of mesenchymal stem cells

In the last few decades, stem cell-based therapies have gained attention worldwide for various diseases and disorders. Adult stem cells, particularly mesenchymal stem cells (MSCs), are preferred due to their significant regenerative potential in cellular therapies and are currently involved in hundreds of clinical trials. Although MSCs have high self-renewal as well as differentiation potential, such abilities are compromised with “advanced age” and “disease status” of the donor. Similarly, cell-based therapies require high cell number for clinical applications that often require in vitro expansion of cells. It is pertinent to note that aged individuals are the main segment of population for stem cell-based therapies, however; autologous use of stem cells for such patients (aged and diseased) does not seem to give optimal results due to their compromised potential. In vitro expansion to obtain large numbers of cells also negatively affects the regenerative potential of MSCs. It is therefore essential to improve the regenerative potential of stem cells compromised due to “in vitro expansion”, “donor age” and “donor disease status” for their successful autologous use. The current review has been organized to address the age and disease depleted function of resident adult stem cells, and the strategies to improve their potential. To combat the problem of decline in the regenerative potential of cells, this review focuses on the strategies that manipulate the cell environment such as hypoxia, heat shock, caloric restriction and preconditioning with different factors.     

Stem cell-based approaches: Possible route to hearing restoration?

Disabling hearing loss is the most common sensorineural disability worldwide. It affects around 466 million people and its incidence is expected to rise to around900 million people by 2050, according to World Health Organization estimates.Most cases of hearing impairment are due to the degeneration of hair cells(HCs)in the cochlea, mechano-receptors that transduce incoming sound information into electrical signals that are sent to the brain. Damage to these cells is mainly caused by exposure to aminoglycoside antibiotics and to some anti-cancer drugs such as cisplatin, loud sounds, age, infections and genetic mutations. Hearing deficits may also result from damage to the spiral ganglion neurons that innervate cochlear HCs. Differently from what is observed in avian and nonmammalian species, there is no regeneration of missing sensory cell types in the adult mammalian cochlea, what makes hearing loss an irreversible process. This review summarizes the research that has been conducted with the aim of developing cell-based strategies that lead to sensory cell replacement in the adult cochlea and, ultimately, to hearing restoration. Two main lines of research are discussed, one directed toward the transplantation of exogenous replacement cells into the damaged tissue, and another that aims at reactivating the regenerative potential of putative progenitor cells in the adult inner ear. Results from some of the studies that have been conducted are presented and the advantages and drawbacks of the various approaches discussed.     

Current advances of stem cell-based therapy for kidney diseases

Kidney diseases are a prevalent health problem around the world. Multidrug therapy used in the current routine treatment for kidney diseases can only delay disease progression. None of these drugs or treatments can reverse the progression to an end-stage of the disease. Therefore, it is crucial to explore novel therapeutics to improve patients’ quality of life and possibly cure, reverse, or alleviate the kidney disease. Stem cells have promising potentials as a form of regenerative medicine for kidney diseases due to their unlimited replication and their ability to differentiate into kidney cells in vitro. Mounting evidences from the administration of stem cells in an experimental kidney disease model suggested that stem cell-based therapy has therapeutic or renoprotective effects to attenuate kidney damage while improving the function and structure of both glomerular and tubular compartments. This review summarises the current stem cell-based therapeutic approaches to treat kidney diseases, including the various cell sources, animal models or in vitro studies. The challenges of progressing from proof-of-principle in the laboratory to widespread clinical application and the human clinical trial outcomes reported to date are also highlighted. The success of cell-based therapy could widen the scope of regenerative medicine in the future.     

Corneal stem cells and tissue engineering: Current advances and future perspectives

Major advances are currently being made in regenerative medicine for cornea. Stem cell-based therapies represent a novel strategy that may substitute conventional corneal transplantation, albeit there are many challenges ahead given the singularities of each cellular layer of the cornea. This review recapitulates the current data on corneal epithelial stem cells, corneal stromal stem cells and corneal endothelial cell progenitors. Corneal limbal autografts containing epithelial stem cells have been transplanted in humans for more than 20 years with great successful rates, and researchers now focus on ex vivo cultures and other cell lineages to transplant to the ocular surface. A small population of cells in the corneal endothelium was recently reported to have self-renewal capacity, although they do not proliferate in vivo. Two main obstacles have hindered endothelial cell transplantation to date: culture protocols and cell delivery methods to the posterior cornea in vivo. Human corneal stromal stem cells have been identified shortly after the recognition of precursors of endothelial cells. Stromal stem cells may have the potential to provide a direct cell-based therapeutic approach when injected to corneal scars. Furthermore, they exhibit the ability to deposit organized connective tissue in vitro and may be useful in corneal stroma engineering in the future. Recent advances and future perspectives in the field are discussed.