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Acute myocardial infarction (AMI) is a common cause of morbidity and mortality worldwide. Severe MI leads to heart failure due to a marked loss of functional cardiomyocytes. First-line treatment for AMI is to reperfuse the occluded coronary artery by PCI as soon as possible. Besides PCI, there are several therapies to reduce the infarct size and improve the cardiac function and remodeling. These are drug therapies such as pharmacological pre- and postconditioning, cytokine therapies, and stem cell therapies. None of these therapies have been clinically developed as a standard treatment for AMI. Among many cell sources for stem cell therapies, the Muse cell is an endogenous non-tumorigenic pluripotent stem cell, which is able to differentiate into cells of all three germ layers from a single cell, suggesting that the Muse cell is a potential cell source for regenerative medicine. Endogenous Muse cell dynamics in the acute phase plays an important role in the prognosis of AMI patients; AMI patients with a higher number of Muse cells in the peripheral blood in the acute phase show more favorable improvement of the cardiac function and remodeling in the chronic phase, suggesting their innate reparative function for the heart. Intravenously administered exogenous Muse cells engrafted preferentially and efficiently to infarct border areas via the S1P-S1PR2 axis and differentiated spontaneously into working cardiomyocytes and vessels, showed paracrine effects, markedly reduced the myocardial infarct size, and delivered long-lasting improvement of the cardiac function and remodeling for 6 months. These findings suggest that Muse cells are reparative stem cells, and thus their clinical application is warranted.

Stroke is defined as a sudden onset of neurologic deficits arising from cerebrovascular complications. It is the second common cause of death around the world and the major cause of disability. Because brain is an organ with complicated neural networks and neurons are highly differentiated, it has been traditionally considered to possess a limited potential for regeneration. The number of stroke patients is increasing, and stroke represents a serious problem from the viewpoint of the national medical economy. Even with the current sophisticated treatments, more than half of stroke patient survivors remain disabled. Therefore, it is imperative to develop a new treatment for promoting functional recovery and repair of the lost neurological circuit. Multilineage-differentiating stress-enduring (Muse) cells are endogenous non-tumorigenic stem cells with pluripotency. After transplantation, Muse cells recognize the injured site through their specific receptor for damage signal, home preferentially into these tissues and spontaneously differentiate into tissue-compatible cells to replace the lost cells, and repair the tissue, delivering functional and structural regeneration. These properties are desirable for the treatment of strokes and advantageous compared to other stem cell therapies. Here, we describe the current status of stem cell therapies for stroke and future possibilities of Muse cell therapy.

Stem cells have fascinated scientists for a long time and huge research efforts have been put into them as they have the potential to regenerate diseased organs. Besides embryonic stem cells (ES) and induced pluripotent stem cells (iPS), it has been postulated that pluripotent stem cells (PSCs) may also exist in various adult tissues. They are thought to be more primitive than the adult stem cells (ASCs), serve as a backup pool to give rise to ASCs and thus play a crucial role in maintaining life-long homeostasis. These PSCs could also be the embryonic stem cells in adult tissues that were proposed to initiate cancers according to the Embryonic Rest Hypothesis put forth in the nineteenth century. However, the very presence of PSCs in adult tissues is mired with controversies. This article is a sincere attempt to review research carried out by various investigators over the last two decades and various attempts to demonstrate their presence in adult tissues. Such adult PSCs could be the ideal stem cell candidates to bring about endogenous regeneration compared to ES/iPS cells grown in Petri dish and also score better over ASCs which in fact are tissue committed progenitors with limited regenerative potential that differentiate from the PSCs. PSCs in adult tissues have remained elusive until now as they possibly get unknowingly discarded due to their small size and inability to pellet at 1000-1200 rpm (250 g). They will likely prove to be a game changer in the field of stem cells biology, for regenerative medicine and for our understanding of cancer initiation.

Abstract Background Human multilineage-differentiating stress enduring (Muse) cells are nontumorigenic endogenous pluripotent-like stem cells that can be easily obtained from various adult or fetal tissues. Regenerative effects of Muse cells have been shown in some disease models. Muse cells specifically home in damaged tissues where they exert pleiotropic effects. Exposition of the small intestine to high doses of irradiation (IR) delivered after radiotherapy or nuclear accident results in a lethal gastrointestinal syndrome (GIS) characterized by acute loss of intestinal stem cells, impaired epithelial regeneration and subsequent loss of the mucosal barrier resulting in sepsis and death. To date, there is no effective medical treatment for GIS. Here, we investigate whether Muse cells can prevent lethal GIS and study how they act on intestinal stem cell microenvironment to promote intestinal regeneration. Methods Human Muse cells from Wharton’s jelly matrix of umbilical cord (WJ-Muse) were sorted by flow cytometry using the SSEA-3 marker, characterized and compared to bone-marrow derived Muse cells (BM-Muse). Under gas anesthesia, GIS mice were treated or not through an intravenous retro-orbital injection of 50,000 WJ-Muse, freshly isolated or cryopreserved, shortly after an 18 Gy-abdominal IR. No immunosuppressant was delivered to the mice. Mice were euthanized either 24 h post-IR to assess early small intestine tissue response, or 7 days post-IR to assess any regenerative response. Mouse survival, histological stainings, apoptosis and cell proliferation were studied and measurement of cytokines, recruitment of immune cells and barrier functional assay were performed. Results Injection of WJ-Muse shortly after abdominal IR highly improved mouse survival as a result of a rapid regeneration of intestinal epithelium with the rescue of the impaired epithelial barrier. In small intestine of Muse-treated mice, an early enhanced secretion of IL-6 and MCP-1 cytokines was observed associated with (1) recruitment of monocytes/M2-like macrophages and (2) proliferation of Paneth cells through activation of the IL-6/Stat3 pathway. Conclusion Our findings indicate that a single injection of a small quantity of WJ-Muse may be a new and easy therapeutic strategy for treating lethal GIS.

Background: Human multilineage-differentiating stress enduring (Muse) cells are nontumorigenic endogenous pluripotent-like stem cells that can be easily obtained from various adult or fetal tissues. Regenerative effects of Muse cells have been shown in some disease models. Muse cells specifically home in damaged tissues where they exert pleiotropic effects. Exposition of the small intestine to high doses of irradiation (IR) delivered after radiotherapy or nuclear accident results in a lethal gastrointestinal syndrome (GIS) characterized by acute loss of intestinal stem cells, impaired epithelial regeneration and subsequent loss of the mucosal barrier resulting in sepsis and death. To date, there is no effective medical treatment for GIS. Here, we investigate whether Muse cells can prevent lethal GIS and study how they act on intestinal stem cell microenvironment to promote intestinal regeneration. Methods: Human Muse cells from Wharton's jelly matrix of umbilical cord (WJ-Muse) were sorted by flow cytometry using the SSEA-3 marker, characterized and compared to bone-marrow derived Muse cells (BM-Muse). Under gas anesthesia, GIS mice were treated or not through an intravenous retro-orbital injection of 50,000 WJ-Muse, freshly isolated or cryopreserved, shortly after an 18 Gy-abdominal IR. No immunosuppressant was delivered to the mice. Mice were euthanized either 24 h post-IR to assess early small intestine tissue response, or 7 days post-IR to assess any regenerative response. Mouse survival, histological stainings, apoptosis and cell proliferation were studied and measurement of cytokines, recruitment of immune cells and barrier functional assay were performed. Results: Injection of WJ-Muse shortly after abdominal IR highly improved mouse survival as a result of a rapid regeneration of intestinal epithelium with the rescue of the impaired epithelial barrier. In small intestine of Muse-treated mice, an early enhanced secretion of IL-6 and MCP-1 cytokines was observed associated with (1) recruitment of monocytes/M2-like macrophages and (2) proliferation of Paneth cells through activation of the IL-6/Stat3 pathway. Conclusion: Our findings indicate that a single injection of a small quantity of WJ-Muse may be a new and easy therapeutic strategy for treating lethal GIS. [ABSTRACT FROM AUTHOR]

Multilineage-differentiating stress-enduring (Muse) cells were discovered in 2010 as a subpopulation of mesenchymal stroma cells (MSCs). Muse cells can self-renew and tolerate severe culturing conditions. These cells can differentiate into three lineage cells spontaneously or in induced medium but do not form teratoma in vitro or in vivo. Central nervous system (CNS) diseases, such as intracerebral hemorrhage (ICH), cerebral infarction, and spinal cord injury are normally disastrous. Despite numerous therapy strategies, CNS diseases are difficult to recover. As a novel kind of pluripotent stem cells, Muse cells have shown great regeneration capacity in many animal models, including acute myocardial infarction, hepatectomy, and acute cerebral ischemia (ACI). After injection into injury sites, Muse cells survived, migrated, and differentiated into functional neurons with synaptic junctions to local neurons and contributed to recovery of function. Furthermore, Muse cell differentiation did not need to be induced pre-transplantation and no tumors were observed post- transplantation. The Muse cell population is promising and may lead to a revolution in regenerative medicine. This review focuses on recent advances regarding the Muse cells therapies in Neurorestoratology and discusses future perspectives in this field.

Since the early days of molecular biology, organ and tissue regeneration represents a challenging medical goal. However, only recently the advances in the understanding of the cellular components have enabled the promise to become a reality. In this vast panorama of new technologies, stem cells have progressively established themselves as the most effective and user-friendly regenerative therapeutic tool. Scientific meetings, workshops, conferences, and forums focused on translational science of regenerative technologies are today blooming all over the world. The audience questions and, even more, the very often controversial and conflicting explanations highlight the great deal of confusion regarding this new discipline that should be considered today a real independent medical specialty, requiring long-term studies and dedication. All the technologies able to separate and concentrate the adipose tissue (AT) and the stromal vascular fraction (SVF) and their related clinical applications need to comply with a complex but still unclear regulatory frame, becoming everyday more severe and restrictive, this limiting their practical use. The aim of this manuscript is to overview the current status of the regulatory frame and few related ethical considerations and to describe the evolution in the way the adipose-derived stromal vascular fraction (SVF) is isolated, extracted, and concentrated, as well as, of the ongoing researches and related future perspectives. Considerations on the most controversial and still unclear points related to the regenerative medicine and surgery, seen from the perspective of a research group who dedicated their entire professional life to this field, are also provided. Level of evidence: Not ratable. [ABSTRACT FROM AUTHOR]