Frontiers in Stem Cell and Regenerative Medicine Research

Epimorphic regeneration is a process by which damaged tissues or severed body parts are restored to the original. This type of sophisticated regeneration is observed in urodeles and fetal mammals. For example, through this process, an amputated limb of a salamander can be restored, by re-growing an exact replica, irrespective of its age. During limb epimorphic regeneration: committed mesenchymal cells at the stump site dedifferentiate, forming a cluster of heterogeneous population of stem cells, known as the blastema. Upon blastema integration, positioning and expansion, constituent cells embark on redifferentiation and remorphogenesis to restore the lost appendage. Similar to epimorphic regeneration is retrodifferentiation in human leukocytes. In response to ligation of monomorphic regions of MHC class II antigens with monoclonal antibody CR3/43, human leukocytes retrodifferentiate into a variety of heterogeneous stem cell types belonging to the mesoderm, ectoderm or endoderm lineage, depending on culture media and conditions. During this process, leukocytes lose lineage-associated markers home and undergo homocytic aggregation, upregulate expression of stem cell antigens, and subsequently redifferentiate to give rise original tissue or, transdifferentiate into a different tissue altogether. The hematopoietic retrodifferentiated stem cells have been shown to engraft an animal host in two proofs of principle clinical studies, demonstrating long-term engraftment and safety in acquired aplastic anaemia, while transient amelioration of beta thalassemia major was also observed. Binding of MHC class II antigens on leukocytes with the monoclonal antibody CR3/43 appears to emulate stress and injury in human tissue in vitro, similar to limb amputation in salamander. The ease by which various stem cell types can be generated from human peripheral blood has allowed the design of various kits to guarantee the specificity, sterility and efficacy of stem cells production for various clinical and research applications. The robustness and efficacy of the retrodifferentiation process in generating unprecedented quantities of stem cells belonging to the three germ layers will enable organ and tissue reconstruction ex vivo, using bio-printing and various scaffold materials. Epimorphic regeneration and retrodifferentiation both have the capacity to recreate and reconstruct tissue with precise positional integration of cells in such a way that will enable us to heal without scars and to understand how to maintain tissue integrity and architecture in the face of a hostile environment.

Regenerative medicine is centred around the premise that progenitor populations can be engineered to give rise to mature cell lineages forming a complex tissue architecture which in turn produces functional organs. The potency of the starting progenitor population is therefore a critical consideration. The mesendoderm is a rare population of cells present in the embryo only at gastrulation. This bipotent population gives rise to the mesoderm and the definitive endoderm and all mature cell types derived from these germ layers. Mesodermal progenitors generate cardiac, smooth and skeletal muscle, as well as the blood and vascular lineages, bone and connective tissue cells. The endoderm is the source of numerous cell lineages with potential utility for regenerative medicine including hepatocytes, pancreatic lineages and the epithelial cells of the respiratory, gastrointestinal and reproductive tracts. The development of numerous organs is dependent upon mesoderm-derived lineages interacting with endodermal-derived cell types. The kidney, adrenal gland, pancreas and genito-urinary tract development all require interactions between mesodermal and endodermal derivative cell types. Here, we describe the unique genetic programmes that lead to mesendoderm formation, the pathways leading to mesoderm and endoderm specification and examples where mature cell types from both germ layers interact to support their mutual development. We will also show how these programmes are being harnessed to direct the differentiation of pluripotent cells in vitro into mesendodermderived cells and tissues which can be used to improve the quality of human life. Finally, we will discuss considerations for combining stem cell differentiation with tissue engineering through 3D bioprinting modalities.

The hematopoietic, or blood-producing, system resides in the bone marrow of adult mammals. This system regulates the production of billions of new blood cells per day in healthy adult humans. Even slight perturbations of this production can lead to severe pathological conditions. One of the first applications of cellular regenerative medicine in clinical practice was the transplantation of bone marrow cells to generate a new, healthy blood production system in compromised patients. The success of bone marrow transplantation is dependent upon the potency of stem cell and progenitor populations within the adult mammalian bone marrow. The utility of hematopoietic stem cell (HSC) transplant has been extended to the treatment of a broad range of hematological diseases and disorders, as well as in the regeneration of the bloodproducing tissue following radiation or chemotherapy. There is a strong push towards the development of vast numbers of mature blood cells in vitro. An in vitro system resulting in the consistent, large-scale production of patient-specific mature erythrocytes from HSCs or erythroid progenitors could alleviate the pressure felt by blood donation agencies. The cells that support blood cell production in the bone marrow and other organs, known collectively as the hematopoietic niche, are critical in blood cell lineage regeneration. The development of novel regenerative therapies to treat myelodysplastic syndromes, anemia, leukemia and other blood diseases deserves attention. Stem, progenitor and supportive cells within the hematopoietic tissues are essential elements of regenerative medicine. The utility, limitation and promise of these populations in regenerative medicine are described here.

Cell-based therapy is a growing field in veterinary medicine and has created a lot of hope and excitements for developing new therapies for degenerative diseases that otherwise cannot be treated by traditional medical approaches. Clinical studies in dogs, cats and horses show promising results indicating that stem cells and other cellbased products may facilitate tissue repair and improve quality of life in companion animals. In this review, different cell based therapies, their risks and benefits and their possible therapeutic use for veterinary medical application will be discussed.

Mesenchymal stem cells (MSCs) are today, the most favoured cellular candidates for regenerative therapeutics. Though discovered early in the 1960s, only recent decades have witnessed extensive research involving MSCs. MSCs, termed as multipotent mesenchymal stromal cells in 2006, by the International Society of Cellular Therapy have gained greater acceptance in view of their ubiquitous presence in tissues, exemption from ethical concerns, clonogenic potential, trilineage differentiation, versatile plasticity and ability to orchestrate host tissue interactions. Biological properties of MSCs that contribute to therapeutic efficiency include facilitating secretion of bioactive factors, induction of cellular recruitment and retention of progenitor faculties. Researchers, however continue to be intrigued by variability in the in vivo identity of MSCs which is influenced by various factors that include tissue of origin, age of MSCs, number of isolates and isolation efficiency, associated metabolic disorders, foetal or adult status, gene expression, protein and transcription factors and allogenic or autologous extract . Although early results in clinical studies are promising, transformation of MSCs into a mature clinically viable option would mean a patient wait.