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Mesenchymal stem cells (MSCs) have been extensively investigated for the treatment of various diseases. The therapeutic potential of MSCs is attributed to complex cellular and molecular mechanisms of action including differentiation into multiple cell lineages and regulation of immune responses via immunomodulation. The plasticity of MSCs in immunomodulation allow these cells to exert different immune effects depending on different diseases. Understanding the biology of MSCs and their role in treatment is critical to determine their potential for various therapeutic applications and for the development of MSC-based regenerative medicine. This review summarizes the recent progress of particular mechanisms underlying the tissue regenerative properties and immunomodulatory effects of MSCs. We focused on discussing the functional roles of paracrine activities, direct cell–cell contact, mitochondrial transfer, and extracellular vesicles related to MSC-mediated effects on immune cell responses, cell survival, and regeneration. This will provide an overview of the current research on the rapid development of MSC-based therapies.

The field of tissue engineering has progressed tremendously over the past few decades in its ability to fabricate functional tissue substitutes for regenerative medicine and pharmaceutical research. Conventional scaffold-based approaches are limited in their capacity to produce constructs with the functionality and complexity of native tissue. Three-dimensional (3D) bioprinting offers exciting prospects for scaffolds fabrication, as it allows precise placement of cells, biochemical factors, and biomaterials in a layer-by-layer process. Compared with traditional scaffold fabrication approaches, 3D bioprinting is better to mimic the complex microstructures of biological tissues and accurately control the distribution of cells. Here, we describe recent technological advances in bio-fabrication focusing on 3D bioprinting processes for tissue engineering from data processing to bioprinting, mainly inkjet, laser, and extrusion-based technique. We then review the associated bioink formulation for 3D bioprinting of human tissues, including biomaterials, cells, and growth factors selection. The key bioink properties for successful bioprinting of human tissue were summarized. After bioprinting, the cells are generally devoid of any exposure to fluid mechanical cues, such as fluid shear stress, tension, and compression, which are crucial for tissue development and function in health and disease. The bioreactor can serve as a simulator to aid in the development of engineering human tissues from in vitro maturation of 3D cell-laden scaffolds. We then describe some of the most common bioreactors found in the engineering of several functional tissues, such as bone, cartilage, and cardiovascular applications. In the end, we conclude with a brief insight into present limitations and future developments on the application of 3D bioprinting and bioreactor systems for engineering human tissue.

Organ and tissue loss through disease and injury motivate the development of therapies that can regenerate tissues and decrease reliance on transplantations. Regenerative medicine, an interdisciplinary field that applies engineering and life science principles to promote regeneration, can potentially restore diseased and injured tissues and whole organs. Since the inception of the field several decades ago, a number of regenerative medicine therapies, including those designed for wound healing and orthopedics applications, have received Food and Drug Administration (FDA) approval and are now commercially available. These therapies and other regenerative medicine approaches currently being studied in preclinical and clinical settings will be covered in this review. Specifically, developments in fabricating sophisticated grafts and tissue mimics and technologies for integrating grafts with host vasculature will be discussed. Enhancing the intrinsic regenerative capacity of the host by altering its environment, whether with cell injections or immune modulation, will be addressed, as well as methods for exploiting recently developed cell sources. Finally, we propose directions for current and future regenerative medicine therapies.

Diabetes mellitus is a metabolic disorder that affects more than 460 million people worldwide. Type 1 diabetes (T1D) is caused by autoimmune destruction of β-cells, whereas type 2 diabetes (T2D) is caused by a hostile metabolic environment that leads to β-cell exhaustion and dysfunction. Currently, first-line medications treat the symptomatic insulin resistance and hyperglycaemia, but do not prevent the progressive decline of β-cell mass and function. Thus, advanced therapies need to be developed that either protect or regenerate endogenous β-cell mass early in disease progression or replace lost β-cells with stem cell-derived β-like cells or engineered islet-like clusters. In this Review, we discuss the state of the art of stem cell differentiation and islet engineering, reflect on current and future challenges in the area and highlight the potential for cell replacement therapies, disease modelling and drug development using these cells. These efforts in stem cell and regenerative medicine will lay the foundations for future biomedical breakthroughs and potentially curative treatments for diabetes.Diabetes is a substantial and increasing health concern. In this Review, Lickert and colleagues discuss the progress made in developing insulin-producing islets using in vitro methods, including which aspects need to be improved in order to use these islets as transplants. Using these islets in laboratory settings could further our understanding of pancreatic function and the mechanisms underlying diabetes.

Key Points This Review describes recent progress in directing human pluripotent stem cells (hPSCs) into specific progeny that could have therapeutic purposes for a range of diseases. It also addresses major hurdles in the transition of hPSC-based cell therapies from the bench to the bedside. Neural induction of hPSCs can be achieved in several ways. Recent protocols use defined neural inducers — such as inhibitors of transforming growth factor-β (TGFβ) and bone morphogenetic protein (BMP) (that is, dual SMAD inhibition) — to greatly enhance the efficiency and the speed of neural induction. The derivation of dopamine neurons from hPSCs has been achieved a decade ago, but the cells did not show good engraftment. Recent data shows that those neurons lacked expression of forkhead box protein A2 (FOXA2), which is a DNA-binding transcription factor that is fundamental for authentic midbrain identity. A novel protocol derives dopamine neurons through a floor plate intermediate, which show genetic, biochemical and physiological features of authentic midbrain neurons. They also survive and ameliorate Parkinson's disease-like behaviour in vivo . Improved protocols for the derivation of medium spiny striatal neurons from hPSCs has been reported, and evidence shows survival and behavioural improvement in a lesion model of Huntington's disease. The derivation of glial cells from hPSCs is faced with the challenge of protracted developmental timing in vitro , which is similar to the in vivo situation. The derivation of oligodendrocytes has been achieved using long-term in vitro cultures; these cells have been grafted in neonatal Shiverer -expressing mice with good cell survival, remyelination and extended lifespan in these mice. The current derivation of non-neural cell types — such as cardiomyocytes, pancreatic islet cells and engraftable haematopoietic stem cells — faces substantial challenges owing to the immature nature of the differentiated cells (for cardiomyocytes), the need for in vivo differentiation (for pancreatic islet cells) and poor in vivo homing (for haematopoietic stem cells). New developments in cell differentiation include the use of potent small molecules that allow the direct manipulation of multiple signalling pathways and, in some cases, the acceleration of differentiation timelines. Other approaches include cell purification and three-dimensional cultures that harness the self-organizing potential of hPSC-derived lineages. Defining cell identity in vitro is a fundamental element in designing directed differentiation strategies and includes expression of cell type-specific markers, transcriptional profiles and assessments of the epigenetic or enhancer landscapes. Assessment of in vivo function includes electrophysiology, the use of genetically encoded calcium sensors, microdialysis and optogenetic techniques, as well as behavioural studies. Autologous cell sources, such as patient-derived induced pluripotent stem cells, are of great interest but currently face substantial hurdles for clinical implementation that are related to safety and regulatory requirements. The translation of direct reprogramming and nuclear transfer strategies are in early stages of development. A spinal cord trial using human embryonic stem cell (hESC)-derived oligodendrocytes has not reported any major adverse effects, although the trial has been abandoned. Ongoing clinical trials using hESC-derived retinal pigment epithelial in eye repair are promising. The derivation of disease-relevant cell types from pluripotent stem cells holds much promise for disease therapy. The recent progress in directed differentiation and the challenges ahead are discussed in this Review. After years of incremental progress, several recent studies have succeeded in deriving disease-relevant cell types from human pluripotent stem cell (hPSC) sources. The prospect of an unlimited cell source, combined with promising preclinical data, indicates that hPSC technology may be on the verge of clinical translation. In this Review, we discuss recent progress in directed differentiation, some of the new technologies that have facilitated the success of hPSC therapies and the remaining hurdles on the road towards developing hPSC-based cell therapies.

The extracellular matrix (ECM) is a complex network with multiple functions, including specific functions during tissue regeneration. Precisely, the properties of the ECM have been thoroughly used in tissue engineering and regenerative medicine research, aiming to restore the function of damaged or dysfunctional tissues. Tissue decellularization is gaining momentum as a technique to obtain potentially implantable decellularized extracellular matrix (dECM) with well-preserved key components. Interestingly, the tissue-specific dECM is becoming a feasible option to carry out regenerative medicine research, with multiple advantages compared to other approaches. This review provides an overview of the most common methods used to obtain the dECM and summarizes the strategies adopted to decellularize specific tissues, aiming to provide a helpful guide for future research development.

As the gap between donors and patients in need of an organ transplant continues to widen, research in regenerative medicine seeks to provide alternative strategies for treatment. One of the most promising techniques for tissue and organ regeneration is decellularization, in which the extracellular matrix (ECM) is isolated from its native cells and genetic material in order to produce a natural scaffold. The ECM, which ideally retains its inherent structural, biochemical, and biomechanical cues, can then be recellularized to produce a functional tissue or organ. While decellularization can be accomplished using chemical and enzymatic, physical, or combinative methods, each strategy has both benefits and drawbacks. The focus of this review is to compare the advantages and disadvantages of these methods in terms of their ability to retain desired ECM characteristics for particular tissues and organs. Additionally, a few applications of constructs engineered using decellularized cell sheets, tissues, and whole organs are discussed.

The ability to replace organs and tissues on demand could save or improve millions of lives each year globally and create public health benefits on par with curing cancer. Unmet needs for organ and tissue preservation place enormous logistical limitations on transplantation, regenerative medicine, drug discovery, and a variety of rapidly advancing areas spanning biomedicine. A growing coalition of researchers, clinicians, advocacy organizations, academic institutions, and other stakeholders has assembled to address the unmet need for preservation advances, outlining remaining challenges and identifying areas of underinvestment and untapped opportunities. Meanwhile, recent discoveries provide proofs of principle for breakthroughs in a family of research areas surrounding biopreservation. These developments indicate that a new paradigm, integrating multiple existing preservation approaches and new technologies that have flourished in the past 10 years, could transform preservation research. Capitalizing on these opportunities will require engagement across many research areas and stakeholder groups. A coordinated effort is needed to expedite preservation advances that can transform several areas of medicine and medical science.

Biomaterials can promote endogenous healing without delivering cells or therapeutics An approach to regenerative medicine that is showing promise involves the use of biomaterials as tissue scaffolds. Biomaterials scaffolds have been used for >20 years in tissue engineering to improve the transplantation of cells and growth factors. More recently, biomaterials that can promote tissue repair and regeneration on their own without the need for delivering cells or other therapeutics have emerged as a potentially powerful paradigm for regenerative medicine.