Adult Cell Types Research Articles

Single cell sequencing of radial glia progeny reveals the diversity of newborn neurons in the adult zebrafish brain.

ABSTRACTZebrafish display widespread and pronounced adult neurogenesis, which is fundamental for their regeneration capability after central nervous system injury. However, the cellular identity and the biological properties of adult newborn neurons are elusive for most brain areas. Here, we have used short-term lineage tracing of radial glia progeny to prospectively isolate newborn neurons from the her4.1+ radial glia lineage in the homeostatic adult forebrain. Transcriptome analysis of radial glia, newborn neurons and mature neurons using single cell sequencing identified distinct transcriptional profiles, including novel markers for each population. Specifically, we detected two separate newborn neuron types, which showed diversity of cell fate commitment and location. Further analyses showed that these cell types are homologous to neurogenic cells in the mammalian brain, identified neurogenic commitment in proliferating radial glia and indicated that glutamatergic projection neurons are generated in the adult zebrafish telencephalon. Thus, we prospectively isolated adult newborn neurons from the adult zebrafish forebrain, identified markers for newborn and mature neurons in the adult brain, and revealed intrinsic heterogeneity among adult newborn neurons and their homology with mammalian adult neurogenic cell types.

Epigenetic metabolites license stem cell states.

It has become clear during recent years that stem cells undergo metabolic remodeling during their activation process. While these metabolic switches take place in pluripotency as well as adult stem cell populations, the rules that govern the switch are not clear. In this review, we summarize some of the transitions in adult and pluripotent cell types and will propose that the key function in this process is the generation of epigenetic metabolites that govern critical epigenetic modifications, and therefore stem cell states.

Single Cell and Single Nucleus RNA-Seq Reveal Cellular Heterogeneity and Homeostatic Regulatory Networks in Adult Mouse Stria Vascularis.

The stria vascularis (SV) generates the endocochlear potential (EP) in the inner ear and is necessary for proper hair cell mechanotransduction and hearing. While channels belonging to SV cell types are known to play crucial roles in EP generation, relatively little is known about gene regulatory networks that underlie the ability of the SV to generate and maintain the EP. Using single cell and single nucleus RNA-sequencing, we identify and validate known and rare cell populations in the SV. Furthermore, we establish a basis for understanding molecular mechanisms underlying SV function by identifying potential gene regulatory networks as well as druggable gene targets. Finally, we associate known deafness genes with adult SV cell types. This work establishes a basis for dissecting the genetic mechanisms underlying the role of the SV in hearing and will serve as a basis for designing therapeutic approaches to hearing loss related to SV dysfunction.

Exploring the Most Promising Stem Cell Therapy in Liver Failure: A Systematic Review.

Background Alternative approaches to transplantation for liver failure are needed. One of the alternative approaches is stem cell therapy. However, stem cell therapy in liver failure is not standardized yet, as every centre have their own methods. This systematic review is aimed at compiling and analyzing the various studies that use stem cells to treat liver failure, to get an insight into potential protocols in terms of safety and efficacy by comparing them to controls. Methods This systematic review was done according to PRISMA guidelines and submitted for registration in PROSPERO (registration number CRD42018106119). All published studies in PubMed/MEDLINE and Cochrane Library, using key words: “human” and “stem cell” AND “liver failure” on 16th June 2018, without time restriction. In addition, relevant articles that are found during full-text search were added. Inclusion criteria included all original articles on stem cell use in humans with liver failure. Data collected included study type, treatment and control number, severity of disease, concomitant therapy, type and source of cells, passage of cells, dose, administration route, repeats, and interval between repeats, outcomes, and adverse events compared to controls. Data were analyzed descriptively to determine the possible causes of adverse reactions, and which protocols gave a satisfactory outcome, in terms of safety and efficacy. Results There were 25 original articles, i.e., eight case studies and 17 studies with controls. Conclusion Among the various adult stem cells that were used in human studies, MSCs from the bone marrow or umbilical cord performed better compared to other types of adult stem cells, though no study showed a complete and sustainable performance in the outcome measures. Intravenous (IV) route was equal to invasive route. Fresh or cryopreserved, and autologous or allogeneic MSCs were equally beneficial; and giving too many cells via intraportal or the hepatic artery might be counterproductive.

Renewed proliferation in adult mouse cochlea and regeneration of hair cells

The adult mammalian inner ear lacks the capacity to divide or regenerate. Damage to inner ear generally leads to permanent hearing loss in humans. Here, we present that reprogramming of the adult inner ear induces renewed proliferation and regeneration of inner ear cell types. Co-activation of cell cycle activator Myc and inner ear progenitor gene Notch1 induces robust proliferation of diverse adult cochlear sensory epithelial cell types. Transient MYC and NOTCH activities enable adult supporting cells to respond to transcription factor Atoh1 and efficiently transdifferentiate into hair cell-like cells. Furthermore, we uncover that mTOR pathway participates in MYC/NOTCH-mediated proliferation and regeneration. These regenerated hair cell-like cells take up the styryl dye FM1-43 and are likely to form connections with adult spiral ganglion neurons, supporting that Myc and Notch1 co-activation is sufficient to reprogram fully mature supporting cells to proliferate and regenerate hair cell-like cells in adult mammalian auditory organs.

An acute immune response underlies the benefit of cardiac stemcell therapy.

Clinical trials using adult stem cells to regenerate damaged heart tissue continue to this day1,2 despite ongoing questions of efficacy and a lack of mechanistic understanding of the underlying biologic effect3. The rationale for these cell therapy trials is derived from animal studies that show a modest but reproducible improvement in cardiac function in models of cardiac ischemic injury4,5. Here we examined the mechanistic basis for cell therapy in mice after ischemia/reperfusion (I/R) injury, and while heart function was enhanced, it was not associated with new cardiomyocyte production. Cell therapy improved heart function through an acute sterile immune response characterized by the temporal and regional induction of CCR2+ and CX3CR1+ macrophages. Intra-cardiac injection of 2 distinct types of adult stem cells, freeze/thaw-killed cells or a chemical inducer of the innate immune response similarly induced regional CCR2+ and CX3CR1+ macrophage accumulation and provided functional rejuvenation to the I/R-injured heart. This selective macrophage response altered cardiac fibroblast activity, reduced border zone extracellular matrix (ECM) content, and enhanced the mechanical properties of the injured area. The functional benefit of cardiac cell therapy is thus due to an acute inflammatory-based wound healing response that rejuvenates the mechanical properties of the infarcted area of the heart.

Advanced Polymers for Three-Dimensional (3D) Organ Bioprinting.

Three-dimensional (3D) organ bioprinting is an attractive scientific area with huge commercial profit, which could solve all the serious bottleneck problems for allograft transplantation, high-throughput drug screening, and pathological analysis. Integrating multiple heterogeneous adult cell types and/or stem cells along with other biomaterials (e.g., polymers, bioactive agents, or biomolecules) to make 3D constructs functional is one of the core issues for 3D bioprinting of bioartificial organs. Both natural and synthetic polymers play essential and ubiquitous roles for hierarchical vascular and neural network formation in 3D printed constructs based on their specific physical, chemical, biological, and physiological properties. In this article, several advanced polymers with excellent biocompatibility, biodegradability, 3D printability, and structural stability are reviewed. The challenges and perspectives of polymers for rapid manufacturing of complex organs, such as the liver, heart, kidney, lung, breast, and brain, are outlined.

Differential Expression of CD49f Discriminates the Independently Emerged Hematopoietic Stem Cells and Erythroid-Biased Progenitors

While hematopoietic stem cells (HSCs) can sustain the production of all types of mature blood cells throughout the life, there also exists HSC-independent hematopoiesis, which partially supports embryonic hematopoiesis and generation of specific types of adult hematopoietic cells (e.g., macrophages). Examples of the HSC-independent hematopoiesis include (i) the primitive wave of hematopoiesis that produces unipotent progenitors for erythrocytes, megakaryocytes or macrophages, and (ii) the "pro-definitive" hematopoiesis that produces multipotent erythro-myeloid progenitors (EMPs). Given that HSCs and HSC-independent progenitors are both derived from endothelial cells in distinct or overlapping hematopoietic sites, tracing their developmental origins and clarifying the regulatory mechanism will enhance our understanding of the profound difference between them and may improve in vitro generation of HSCs. Human HSCs have been refined based on the expression of CD49f (ITGA6). In combination with other HSC markers (CD34+CD38-CD45RA-CD43+CD90+), high expression of CD49f identifies long-term multilineage engrafting HSCs, whereas the cells with low CD49f represent a subtype of hematopoietic progenitor cells (HPCs) that possess transient engrafting activity. Meanwhile, CD49f has also been shown to be heterogeneously expressed in hemogenic endothelial cells (HECs), which give rise to both HSCs and EMPs via endothelial-to-hematopoietic transition (EHT). Thus, determining the changes (i.e., persistence, gain or loss) of CD49f expression during EHT is a key step in tracing the origins of HSCs and HSC-independent HPCs. In this study, using an in vitro system of HSC differentiation from human embryonic stem cells (hESCs), we observed that, while CD49f is highly expressed in all hESCs, only a portion of HECs express CD49f. Importantly, live cell imaging analysis revealed that CD49f expression persists during EHT, which is accompanied by initiating CD43 expression. To test whether the differential CD49f expression is associated with HSC versus HPC functions, we sorted the CD49fhigh and CD49flow cells and performed colony forming assay and gene expression profiling. The results showed that the CD49fhigh cells have multilineage potential, whereas the CD49flow cells lack lymphoid potential but show a strong erythroid preference. Gene expression analysis confirmed that the CD49fhigh and CD49flow cells represent HSCs and erythroid-biased HPCs, respectively, and that the Wnt and Notch signaling pathways may play a role in their functions. Collectively, these observations suggest that the CD49fhigh and the CD49flow cells are concurrently derived from the CD49fhigh and CD49flow HECs, thus modeling the in vivo generation of HSCs and HSC-independent HPCs. Based on the in vitro observations, we proposed that CD49f in vivo may also specify the distinct HSPCs emerged at different developmental stages/sites. To test this hypothesis, we isolated mouse primitive HPCs, EMPs and definitive HSCs, as well as their parental HECs, from yolk sac, embryo, and aorta-gonad-mesonephros (AGM) of different embryonic stages and determined their CD49f expression. The results showed that the primitive erythroid progenitors have lowest, whereas the definitive AGM HSCs have highest, CD49f levels; this trend was also observed in the related HECs isolated from various stages/sites. Thus, it is likely that the embryonic hematopoiesis is recapitulated, at least partially, by the in vitro system in terms of the sequential emergence of HSPCs ranging from unipotent erythroid progenitors to multipotent definitive HSCs, and this may also underlie the situation that EMPs and HSCs can be produced at the same stage/site but independently from different HECs. In summary, using the in vitro HSC differentiation system, we found that the differential expression of CD49f discriminates HSCs and HSC-independent progenitors, which are concurrently emerged from HECs. The persistent CD49f expression during EHT suggests that the fates of HSCs and HSC-independent HPCs are pre-defined in their parental HECs. Combining our in vivo data, the differential expression of CD49f also provide a possible regulatory mechanism for the multi-wave hematopoiesis. Further exploring the function and mechanism of CD49f in these regulations should be important for fully understanding the precisely regulated HSC generation and activities. Disclosures No relevant conflicts of interest to declare.

Investigation of telomeres in Egyptian patients with bone marrow failure

Background and aim for the work: Bone marrow failure (BMF) is the inability of the bone marrow to produce an adequate number of peripheral blood cells. BMF included inherited and acquired conditions. The telomerase complex maintains telomere length (TL) in embryonic cells and in few adult cell types such as germ cells, stem cells, T lymphocytes, and monocytes. All the other adult cells, including blood cells, show a progressive reduction in telomere length, which correlates with the age and rate of cell proliferation. Our study aims to evaluate the utility of Real-Time Quantitative-Polymerase Chain Reaction (RQ-PCR) in measuring the relative telomere length and to investigate its correlation with the clinicopathological data of the Egyptian BMF patients. Materials and methods: The study included 3 groups: a group of inherited BMF (25 patients), a group of acquired BMF (10 patients) and a third healthy control group (15 cases). The relative telomere length (RTL) is evaluated for them using RQ-PCR. Results: We have found a significant difference in RTL between all BMF patients and healthy controls (P value= 0.001), there was a significant difference in RTL between inherited BMF patients and its age-matched controls (P value=0.009), also a significant difference between acquired BMF patients and its age-matched controls (P value= 0.034). However, there was no significant difference between inherited and acquired BMF patients (P value= 0.479). On the other hand, we find an association between RTL and lymphocyte count (P value= 0.032) in inherited BMF patients. While another association observed with RTL and red blood cell count (RBCs) in acquired BMF patients (P value= 0.048). There was no significant correlation with RTL and the overall survival or prognosis of those patients. Conclusion: We conclude that the telomere lengths are significantly altered in Egyptian BMF patients, either whether inherited or acquired compared to the control group, with some hematological changes.

GDNF enhances the anti-inflammatory effect of human adipose-derived mesenchymal stem cell-based therapy in renal interstitial fibrosis.

Adipose-derived mesenchymal stem cells (AMSCs) are a type of adult stem cell from the mesoderm with the capacity to migrate and differentiate into other cell lineages. As a morphogenetic state of stem cells, glial-derived neurotrophic factor (GDNF) has been found to promote cell proliferation and differentiation of stem cells. The aims of our study were to investigate the biological activity of AMSCs and whether the GDNF gene can enhance the anti-inflammatory properties of stem cells. In this study, stable proliferative GDNF-overexpressing AMSC lines were successfully established and the AMSCs/GDNF-AMSCs were cocultured with macrophages (Mφ) derived from THP-1 cells in a transwell system. The mRNA expression levels of tumor necrosis factor-alpha (TNF-α), inducible nitric oxide synthase (iNOS), interleukin (IL)-10 and IL-4 were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR). In addition, the expressions of CD163 and CD206, two markers of M2 macrophages, were detected with flow cytometric analysis. In animal experiments, AMSCs/GDNF-AMSCs (5×105) were administered to unilateral ureteral obstruction (UUO) nude mice for 3 or 7 days. The expression levels of cyclooxygenase-2 (COX-2), IL-6, transforming growth factor β1 (TGF-β1) and α-Smooth muscle actin (α-SMA) were determined by Western blotting. Renal pathological changes of all groups were observed by hematoxylin and eosin (HE) and Masson staining. In conclusion, in vitro cultured AMSCs induced a shift in macrophage phenotype from the inflammatory (M1) phenotype to the reparative (M2) phenotype. In the UUO model, AMSC treatment was conducive to the recovery of renal function and interstitial fibrosis. Therefore, we determined that AMSC therapy could promote the phenotypic transformation of macrophages and reduce the progression of renal fibrosis by suppressing inflammation. GDNF could enhance the anti-inflammatory effect of AMSCs.

Therapeutic angiogenesis by stem cell: new hope for the ischemic limbs

Critical limb ischemia in an intractable condition associated with high level of amputation, leading to low quality of life increase morbidity and mortality. It is often not treated by standard therapeutic modalities. Neoangiogenesis has been proposed as a novel method of treatment of such patients. Vascular Endothelial Growth Factor (VEGF) and Cytokine Fibroblast growth Factor (FGF1) have been shown to elicit neoangiogesis. Stem cells are progenitor cells which can differentiate in vivo into different type of cells. Collateral vessel formation after stem cell therapy. A case of 50 years old male, diabetic, hypertensive with dry gangrene of tip of left ring finger was treated with stem cell therapy after proper counseling. He received the therapy in the form of SVF (Stromal Vascular Fraction) from adipose tissue by local injection in the territory of the affected vessels. Following monitoring parameters were reported, improved wound status, local temperature change, oxygen saturation change in the ischemic zone. Outcome of stem cell therapy in this case including the rest pain disappeared at 14 days and the finger becomes warmed by 5°C in 3 weeks. The gangrenous area healed in 3 months. Amputation was averted. Angiogenesis is a complex process leading to new blood vessels formation. Mesenchymal stem cells (MSCs) are a type of adult stem cell which has an immunomodulatory effect. Stem cell therapy has been used to improve limb Vascularity. Stem Cells are likely to be an important modality to treat critical limb ischemia.
 CBMJ 2019 July: Vol. 08 No. 02 P: 40-46

GPR56 AND GPR97 PLAY REDUNDANT ROLES IN REGULATING HEMATOPOIESIS

Hematopoietic stem cells (HSCs) are responsible for the lifelong production and maintenance of adult blood cell types. They arise from the aorta at the embryonic day (E) 10.5 from a subset of endothelial cells that undergo to endothelial-to-hematopoietic transition (EHT). Our lab discovered that a G-coupled receptor protein, Gpr56, is required for the generation of HSCs in zebrafish. However, its role in mammalian hematopoiesis remains controversial. We investigate the functional role of Gpr56 in vitro using our mouse Gata2Venus (G2V) embryonic stem cell (ESC) line which allows us to highly enrich for hematopoietic progenitor cells (HPCs). G2V.G56-/-. We tested the Gpr56 loss of function by generating a full knock out (KO) Gpr56 mouse G2V (G2V.G56-/-) ESC line. The in vitro examination of phenotypic hematopoietic cell production by FACS and colony forming unit-culture (CFU-C) assay reported an increase in hematopoietic cells (HC) and HPCs production from G2V.G56-/- ESC as compared to G2V ESC. Further analyses performed on cell-sorted HPC population showed that another GPR protein, Gpr97 (located in the same locus), is highly expressed when Gpr56 is deleted. This led us to generate a novel G2V Gpr56/Gpr97 double knockout (G2V.G56/97-/-) ESC line. The in vitro differentiation of the G2V.G56/97-/- revealed a significant decrease in HPCs, supporting the idea that a compensatory mechanism by Gpr97 is taking place when Gpr56 is absent. Preliminary in vivo data using a Gpr56 conditional KO mouse model corroborates our hypothesis. The data demonstrate that the Gpr97 performs a redundant function upon deletion of Gpr56 in the HS/PC population and the deletion of both Gpr56 and Gpr97 is sufficient to impair the production of HS/PC and HC in vitro. We conclude that GPR signalling through Gpr56 and/or Gpr97 is required for HPC production.

Induced pluripotent stem cells, a giant leap for mankind therapeutic applications.

Induced pluripotent stem cells (iPSC) technology has propelled the field of stem cells biology, providing new cells to explore the molecular mechanisms of pluripotency, cancer biology and aging. A major advantage of human iPSC, compared to the pluripotent embryonic stem cells, is that they can be generated from virtually any embryonic or adult somatic cell type without destruction of human blastocysts. In addition, iPSC can be generated from somatic cells harvested from normal individuals or patients, and used as a cellular tool to unravel mechanisms of human development and to model diseases in a manner not possible before. Besides these fundamental aspects of human biology and physiology that are revealed using iPSC or iPSC-derived cells, these cells hold an immense potential for cell-based therapies, and for the discovery of new or personalized pharmacological treatments for many disorders. Here, we review some of the current challenges and concerns about iPSC technology. We introduce the potential held by iPSC for research and development of novel health-related applications. We briefly present the efforts made by the scientific and clinical communities to create the necessary guidelines and regulations to achieve the highest quality standards in the procedures for iPSC generation, characterization and long-term preservation. Finally, we present some of the audacious and pioneer clinical trials in progress with iPSC-derived cells.

Cell Types of the Human Retina and Its Organoids at Single-Cell Resolution: Developmental Convergence, Transcriptomic Identity, and Disease Map

How closely human organoids recapitulate cell-type diversity and cell-type maturation of their target organs is not well understood. We developed human retinal organoids with multiple nuclear and synaptic layers. We sequenced the RNA of 158,844 single cells from these organoids at six developmental time points and from the periphery, fovea, pigment epithelium and choroid of light-responsive adult human retinas, and performed histochemistry. Cell types in organoids matured in vitro to a stable ‘developed’ state at a rate similar to human retina development in vivo and the transcriptomes of organoid cell types converged towards the transcriptomes of adult peripheral retinal cell types. The expression of disease-associated genes was significantly cell-type specific in adult retina and cell-type specificity was retained in organoids. We implicate unexpected cell types in diseases such as macular degeneration. This resource identifies cellular targets for studying disease mechanisms in organoids and for targeted repair in adult human retinas.

Role of c-Kit in Myocardial Regeneration and Aging.

c-Kit, a type III receptor tyrosine kinase (RTK), is involved in multiple intracellular signaling whereby it is mainly considered a stem cell factor receptor, which participates in vital functions of the mammalian body, including the human. Furthermore, c-kit is a necessary yet not sufficient marker to detect and isolate several types of tissue-specific adult stem cells. Accordingly, c-kit was initially used as a marker to identify and enrich for adult cardiac stem/progenitor cells (CSCs) that were proven to be clonogenic, self-renewing and multipotent, being able to differentiate into cardiomyocytes, endothelial cells and smooth muscle cells in vitro as well as in vivo after myocardial injury. Afterwards it was demonstrated that c-kit expression labels a heterogenous cardiac cell population, which is mainly composed by endothelial cells while only a very small fraction represents CSCs. Furthermore, c-kit as a signaling molecule is expressed at different levels in this heterogenous c-kit labeled cardiac cell pool, whereby c-kit low expressers are enriched for CSCs while c-kit high expressers are endothelial and mast cells. This heterogeneity in cell composition and expression levels has been neglected in recent genetic fate map studies focusing on c-kit, which have claimed that c-kit identifies cells with robust endothelial differentiation potential but with minimal if not negligible myogenic commitment potential. However, modification of c-kit gene for Cre Recombinase expression in these Cre/Lox genetic fate map mouse models produced a detrimental c-kit haploinsufficiency that prevents efficient labeling of true CSCs on one hand while affecting the regenerative potential of these cells on the other. Interestingly, c-kit haploinsufficiency in c-kit-deficient mice causes a worsening myocardial repair after injury and accelerates cardiac aging. Therefore, these studies have further demonstrated that adult c-kit-labeled CSCs are robustly myogenic and that the adult myocardium relies on c-kit expression to regenerate after injury and to counteract aging effects on cardiac structure and function.

Role of mesenchymal stem cell-derived soluble factors and folic acid in wound healing.

Background/aimMesenchymal stem cells (MSCs) are a type of adult stem cell consisting of a heterogeneous subset of stromal stem cells that can be isolated from adult tissues. Folic acid is another important contributor to tissue regeneration and repair, which affects the synthesis of some building block molecules used for wound healing. In this study, we examine the effect of folic acid and MSC-derived soluble factors in the wound healing model.Materials and methodsHuman umbilical vein endothelial cells (HUVECs) and bone marrow-derived MSCs (BMSCs) were cultured for this study. Cell proliferation analysis was done with xCELLigence RTCA. After 48 h of cultivation, the cell culture medium was collected as MSC conditional medium containing mesenchymal stem cell-derived soluble factors (MDFs). Different concentrations of MDFs (12%, 25%, 50%, 75%, and 100%) were applied to the HUVEC cell line. Folic acid (25, 30, 50, 60, 75, 90, and 100 µM) was tested by application of three different groups (control, 25 µM folic acid, 625 µM folic acid inhibitors) for proliferation on the HUVEC cell line. The combined effects of folic acid and MDFs were tested on the HUVEC cell line with 25 µM folic acid and 50 µM MDFs. All data were statistically analyzed using SPSS 15.0 for Windows.ResultsSignificant differences were observed between controls and cells treated with folic acid, as well as between controls and both folic acid and MDFs (P < 0.05). Among the treated groups, the fastest wound closure rate was seen in cells treated with both folic acid and MDFs.ConclusionThe results show that both folic acid and MDFs increased the wound healing rate in HUVECs when they were used separately. The strongest benefits were seen in treatment using folic acid and MDFs together.

Immunomodulatory Effects of TGF-β Family Signaling within Intestinal Epithelial Cells and Carcinomas.

TGF-β superfamily signaling is responsible for many critical cellular functions including control of cell growth, cell proliferation, cell differentiation, and apoptosis. TGF-β appears to be critical in gastrulation, embryonic development, and morphogenesis, and it retains pleiotropic roles in many adult tissues and cell types in a highly context-dependent manner. While TGF-β signaling within leukocytes is known to have an immunosuppressive role, its immunomodulatory effects within epithelial cells and epithelial cancers is less well understood. Recent data has emerged that suggests TGF-β pathway signaling within epithelial cells may directly modulate pro-inflammatory chemokine/cytokine production and resultant leukocyte recruitment. This immunomodulation by epithelial TGF-β pathway signaling may directly impact tumorigenesis and tumor progression through modulation of the epithelial microenvironment, although causal pathways responsible for such an observation remain incompletely investigated. This review presents the published literature as it relates to the immunomodulatory effects of TGF-β family signaling within intestinal epithelial cells and carcinomas.

A boost towards totipotency for stem cells

Embryonic stem cells derived from the inner cell mass can differentiate to all embryonic lineages of any adult cell type and to a limited extent to extra-embryonic tissues. A study now allows the generation of pig and human stem cells with enhanced differentiation potential towards all embryonic and extra-embryonic fates, one step closer to the totipotent state of the fertilized egg.

Quiescence Entry, Maintenance, and Exit in Adult Stem Cells.

Cells of unicellular and multicellular eukaryotes can respond to certain environmental cues by arresting the cell cycle and entering a reversible state of quiescence. Quiescent cells do not divide, but can re-enter the cell cycle and resume proliferation if exposed to some signals from the environment. Quiescent cells in mammals and humans include adult stem cells. These cells exhibit improved stress resistance and enhanced survival ability. In response to certain extrinsic signals, adult stem cells can self-renew by dividing asymmetrically. Such asymmetric divisions not only allow the maintenance of a population of quiescent cells, but also yield daughter progenitor cells. A multistep process of the controlled proliferation of these progenitor cells leads to the formation of one or more types of fully differentiated cells. An age-related decline in the ability of adult stem cells to balance quiescence maintenance and regulated proliferation has been implicated in many aging-associated diseases. In this review, we describe many traits shared by different types of quiescent adult stem cells. We discuss how these traits contribute to the quiescence, self-renewal, and proliferation of adult stem cells. We examine the cell-intrinsic mechanisms that allow establishing and sustaining the characteristic traits of adult stem cells, thereby regulating quiescence entry, maintenance, and exit.

Rescue of degenerating neurons and cells by stem cell released molecules: using a physiological renormalization strategy.

Evidence suggests that adult stem cell types and progenitor cells act collectively in a given tissue to maintain and heal organs, such as muscle, through a release of a multitude of molecules packaged into exosomes from the different cell types. Using this principle for the development of bioinspired therapeutics that induces homeostatic renormalization, here we show that the collection of molecules released from four cell types, including mesenchymal stem cells, fibroblast, neural stem cells, and astrocytes, rescues degenerating neurons and cells. Specifically, oxidative stress induced in a human recombinant TDP‐43‐ or FUS‐tGFP U2OS cell line by exposure to sodium arsenite was shown to be significantly reduced by our collection of molecules using in vitro imaging of FUS and TDP‐43 stress granules. Furthermore, we also show that the collective secretome rescues cortical neurons from glutamate toxicity as evidenced by increased neurite outgrowth, reduced LDH release, and reduced caspase 3/7 activity. These data are the first in a series supporting the development of stem cell‐based exosome systems therapeutics that uses a physiological renormalization strategy to treat neurodegenerative diseases.