A Mystery Unraveled: Non-tumorigenic pluripotent stem cells in human adult tissues

Embryonic stem cells and induced pluripotent stem cells have emerged as the gold standard of pluripotent stem cells and the class of 10 stem cell with the highest potential for contribution to regenerative and therapeutic application; however, their translational use is often impeded by teratoma formation, commonly associated with pluripotency. We discuss a population of nontumorigenic pluripotent stem cells, termed Multilineage Differentiating Stress Enduring (Muse) cells, which offer an innovative and 15 exciting avenue of exploration for the potential treatment of various human diseases. Areas covered: This review discusses the origin of Muse cells, describes in detail their various unique characteristics, and considers future avenues of their application and investigation with respect to what is currently known 20 of adult pluripotent stem cells in scientific literature. We begin by defining cell potency, then discussing both mesenchymal and various reported populations of pluripotent stem cells, and finally, delving into Muse cells and what sets them apart from their contemporaries. Expert opinion: Muse cells derived from adipose tissue (Muse-AT) are 25 efficiently, routinely and painlessly isolated from human lipoaspirate material, exhibit tripoblastic differentiation both spontaneously and under media-specific induction, and do not form teratomas. We describe qualities specific to Muse-ATcells and their potential impact on the field of regenerative medicine and cell therapy.Fil: Simerman, Ariel A.. University of California; Estados UnidosFil: Perone, Marcelo Javier. University of California; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires; ArgentinaFil: Gimeno, Maria Laura. University of California; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires; ArgentinaFil: Dumesic, Daniel A.. University of California; Estados UnidosFil: Chazenblak, Gregorio D.. University of California; Estados Unido

Novel Pathway of Adipogenesis through Cross-Talk between Adipose Tissue Macrophages, Adipose Stem Cells and Adipocytes: Evidence of Cell Plasticity

INTRODUCTION: Previous studies highlight a complex relationship between lineage and phenotype for adipose tissue macrophages (ATMs), adipose stem cells (ASCs), and adipocytes, suggesting a high degree of plasticity of these cells. In the present study, using a novel co-culture system, we further characterized the interaction between ATMs, ASCs and adipocytes. RESEARCH DESIGN AND METHODS: Human adipocytes and the stromal vascular fraction containing ATMs and ASCs were isolated from human adipose tissue and co-cultured for 24 hours. FACS was used to characterize ATMs and ASCs before and after co-culture. Preadipocytes generated after co-culture were characterized by immunostaining for DLK (preadipocytes), CD14 and CD68 (ATMs), CD34 (ASCs), and Nile Red staining for lipid drops. qRT-PCR was used to quantify adipogenic markers such as C/EBPα and PPARγ. A novel fluorescent nanobead lineage tracing method was utilized before co-culture where fluorescent nanobeads were internalized by CD68 (+) ATMs. RESULTS: Co-culture of adipocytes with ATMs and ASCs increased the formation of new preadipocytes, thereby increasing lipid accumulation and C/EBPα and PPARγ gene expression. Preadipocytes originating after co-culture were positive for markers of preadipocytes, ATMs and ASCs. Moreover, fluorescent nanobeads were internalized by ATMs before co-culture and the new preadipocytes formed after co-culture also contained fluorescent nanobeads, suggesting that new preadipocytes originated in part from ATMs. The formation of CD34(+)/CD68(+)/DLK (+) cell spheres supported the interaction of ATMs, ASCs and preadipocytes. CONCLUSIONS: Cross-talk between adipocytes, ATMs and ASCs promotes preadipocyte formation. The regulation of this novel adipogenic pathway involves differentiation of ATMs to preadipocytes. The presence of CD34(+)/CD68(+)/DLK(+) cells grouped in spheres suggest that paracrine interactions between these cell types plays an important role in the generation and proliferation of new preadipocytes. This phenomenon may reflect the in vivo plasticity of adipose tissue in which ATMs play an additional role during inflammation and other disease states. Understanding this novel pathway could influence adipogenesis, leading to new treatments for obesity, inflammation, and type 2 diabetes

Muse Cells: Nontumorigenic Pluripotent Stem Cells Present in Adult Tissues—A Paradigm Shift in Tissue Regeneration and Evolution

Muse cells are a novel population of nontumorigenic pluripotent stem cells, highly resistant to cellular stress. These cells are present in every connective tissue and intrinsically express pluripotent stem markers such as Nanog, Oct3/4, Sox2, and TRA1-60. Muse cells are able to differentiate into cells from all three embryonic germ layers both spontaneously and under media-specific induction. Unlike ESCs and iPSCs, Muse cells exhibit low telomerase activity and asymmetric division and do not undergo tumorigenesis or teratoma formation when transplanted into a host organism. Muse cells have a high capacity for homing into damaged tissue and spontaneous differentiation into cells of compatible tissue, leading to tissue repair and functional restoration. The ability of Muse cells to restore tissue function may demonstrate the role of Muse cells in a highly conserved cellular mechanism related to cell survival and regeneration, in response to cellular stress and acute injury. From an evolutionary standpoint, genes pertaining to the regenerative capacity of an organism have been lost in higher mammals from more primitive species. Therefore, Muse cells may offer insight into the molecular and evolutionary bases of autonomous tissue regeneration and elucidate the molecular and cellular mechanisms that prevent mammals from regenerating limbs and organs, as planarians, newts, zebrafish, and salamanders do

Polycystic ovary syndrome as a plausible evolutionary outcome of metabolic adaptation

Abstract As a common endocrinopathy of reproductive-aged women, polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, oligo-anovulation and polycystic ovarian morphology. It is linked with insulin resistance through preferential abdominal fat accumulation that is worsened by obesity. Over the past two millennia, menstrual irregularity, male-type habitus and sub-infertility have been described in women and confirm that these clinical features of PCOS were common in antiquity. Recent findings in normal-weight hyperandrogenic PCOS women show that exaggerated lipid accumulation by subcutaneous (SC) abdominal stem cells during development to adipocytes in vitro occurs in combination with reduced insulin sensitivity and preferential accumulation of highly-lipolytic intra-abdominal fat in vivo. This PCOS phenotype may be an evolutionary metabolic adaptation to balance energy storage with glucose availability and fatty acid oxidation for optimal energy use during reproduction. This review integrates fundamental endocrine-metabolic changes in healthy, normal-weight PCOS women with similar PCOS-like traits present in animal models in which tissue differentiation is completed during fetal life as in humans to support the evolutionary concept that PCOS has common ancestral and developmental origins.http://deepblue.lib.umich.edu/bitstream/2027.42/173711/1/12958_2021_Article_878.pd

Endocrine–metabolic dysfunction in polycystic ovary syndrome: an evolutionary perspective

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, oligo-anovulation and polycystic ovarian morphology, with metabolic dysfunction from insulin resistance and abdominal fat accumulation worsened by obesity. As ancestral traits, these features could have favored abdominal fat deposition for energy use during starvation, but have evolved into different PCOS phenotypes with variable metabolic dysfunction. Adipose dysfunction in PCOS from hyperandrogenemia and hyperinsulinemia likely constrains subcutaneous (SC) fat storage, promoting lipotoxicity through ectopic lipid accumulation and oxidative stress, insulin resistance and inflammation in non-adipose tissue. Recent findings of inherently exaggerated SC abdominal stem cell development to adipocytes in women with PCOS, and PCOS-like traits in adult female monkeys with natural hyperandrogenemia, imply common ancestral origins of PCOS in both human and nonhuman primates

Polycystic ovary syndrome as a plausible evolutionary outcome of metabolic adaptation.

As a common endocrinopathy of reproductive-aged women, polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, oligo-anovulation and polycystic ovarian morphology. It is linked with insulin resistance through preferential abdominal fat accumulation that is worsened by obesity. Over the past two millennia, menstrual irregularity, male-type habitus and sub-infertility have been described in women and confirm that these clinical features of PCOS were common in antiquity. Recent findings in normal-weight hyperandrogenic PCOS women show that exaggerated lipid accumulation by subcutaneous (SC) abdominal stem cells during development to adipocytes in vitro occurs in combination with reduced insulin sensitivity and preferential accumulation of highly-lipolytic intra-abdominal fat in vivo. This PCOS phenotype may be an evolutionary metabolic adaptation to balance energy storage with glucose availability and fatty acid oxidation for optimal energy use during reproduction. This review integrates fundamental endocrine-metabolic changes in healthy, normal-weight PCOS women with similar PCOS-like traits present in animal models in which tissue differentiation is completed during fetal life as in humans to support the evolutionary concept that PCOS has common ancestral and developmental origins

Pluripotent nontumorigenic multilineage differentiating stress enduring cells (Muse cells): a seven-year retrospective

Abstract Multilineage differentiating stress enduring (Muse) cells, discovered in the spring of 2010 at Tohoku University in Sendai, Japan, were quickly recognized by scientists as a possible source of pluripotent cells naturally present within mesenchymal tissues. Muse cells normally exist in a quiescent state, singularly activated by severe cellular stress in vitro and in vivo. Muse cells have the capacity for self-renewal while maintaining pluripotent cell characteristics indicated by the expression of pluripotent stem cell markers. Muse cells differentiate into cells representative of all three germ cell layers both spontaneously and under media-specific induction. In contrast to embryonic stem and induced pluripotent stem cells, Muse cells exhibit low telomerase activity, a normal karyotype, and do not undergo tumorigenesis once implanted in SCID mice. Muse cells efficiently home into damaged tissues and differentiate into specific cells leading to tissue regeneration and functional recovery as described in different animal disease models (i.e., fulminant hepatitis, muscle degeneration, skin ulcers, liver cirrhosis, cerebral stroke, vitiligo, and focal segmental glomerulosclerosis). Circulating Muse cells have been detected in peripheral blood, with higher levels present in stroke patients during the acute phase. Furthermore, Muse cells have inherent immunomodulatory properties, which could contribute to tissue generation and functional repair in vivo. Genetic studies in Muse cells indicate a highly conserved cellular mechanism as seen in more primitive organisms (yeast, Saccharomyces cerevisiae, Caenorhabditis elegans, chlamydomonas, Torpedo californica, drosophila, etc.) in response to cellular stress and acute injury. This review details the molecular and cellular properties of Muse cells as well as their capacity for tissue repair and functional recovery, highlighting their potential for clinical application in regenerative medicine

Pluripotent nontumorigenic multilineage differentiating stress enduring cells (Muse cells): a seven-year retrospective.

Multilineage differentiating stress enduring (Muse) cells, discovered in the spring of 2010 at Tohoku University in Sendai, Japan, were quickly recognized by scientists as a possible source of pluripotent cells naturally present within mesenchymal tissues. Muse cells normally exist in a quiescent state, singularly activated by severe cellular stress in vitro and in vivo. Muse cells have the capacity for self-renewal while maintaining pluripotent cell characteristics indicated by the expression of pluripotent stem cell markers. Muse cells differentiate into cells representative of all three germ cell layers both spontaneously and under media-specific induction. In contrast to embryonic stem and induced pluripotent stem cells, Muse cells exhibit low telomerase activity, a normal karyotype, and do not undergo tumorigenesis once implanted in SCID mice. Muse cells efficiently home into damaged tissues and differentiate into specific cells leading to tissue regeneration and functional recovery as described in different animal disease models (i.e., fulminant hepatitis, muscle degeneration, skin ulcers, liver cirrhosis, cerebral stroke, vitiligo, and focal segmental glomerulosclerosis). Circulating Muse cells have been detected in peripheral blood, with higher levels present in stroke patients during the acute phase. Furthermore, Muse cells have inherent immunomodulatory properties, which could contribute to tissue generation and functional repair in vivo. Genetic studies in Muse cells indicate a highly conserved cellular mechanism as seen in more primitive organisms (yeast, Saccharomyces cerevisiae, Caenorhabditis elegans, chlamydomonas, Torpedo californica, drosophila, etc.) in response to cellular stress and acute injury. This review details the molecular and cellular properties of Muse cells as well as their capacity for tissue repair and functional recovery, highlighting their potential for clinical application in regenerative medicine