Type 2 diabetes (T2D) is a polygenic metabolic disorder characterized by insulin resistance in peripheral tissues and impaired insulin secretion by the pancreas. While the decline in insulin production and secretion was previously attributed to apoptosis of insulin-producing β-cells, recent studies indicate that β-cell apoptosis rates are relatively low in diabetes. Instead, β-cells primarily undergo dedifferentiation, a process where they lose their specialized identity and transition into non-functional endocrine progenitor-like cells, ultimately leading to β-cell failure. The underlying mechanisms driving β-cell dedifferentiation remain elusive due to the intricate interplay of genetic factors and cellular stress. Understanding these mechanisms holds the potential to inform innovative therapeutic approaches aimed at reversing β-cell dedifferentiation in T2D. This review explores the proposed drivers of β-cell dedifferentiation leading to β-cell failure, and discusses current interventions capable of reversing this process, thus restoring β-cell identity and function.

BACKGROUND: Processing speed (PS) deficits represent a fundamental aspect of cognitive impairment, evident not only in schizophrenia but also in individuals undergoing their first episode of psychosis (FEP) and their unaffected first-degree relatives. Heterogeneity in tests assessing PS reflects the participation of motor and cognitive subcomponents to varying degrees. We aim to explore differences in performance of the subcomponents of PS in FEP patients, parents, siblings, and controls.
METHODS: Results from tests, including Trail Making Test part A and part B, Digit Symbol Coding Test, Grooved Pegboard Test, and Stroop Word and Stroop Color subtests, were obtained from 133 FEP patients, 146 parents, and 202 controls. Exploratory factor analysis (EFA) was employed in controls to establish the structure, followed by confirmatory factor analysis (CFA) to verify if the other groups share this structure.
RESULTS: EFA revealed a two-factor model: Factor 1 for the motor subcomponent and Factor 2 for the cognitive subcomponent. Subsequently, CFA indicated a good fit for the remaining groups with differences in the relationship between the factors.
CONCLUSIONS: Differences in the relationships of factors within a common structure suggest the involvement of different compensatory strategies among groups, providing insights into the underlying mechanisms of PS deficits in patients and relatives.

The pathogeneses of type 1 and type 2 diabetes involve the progressive loss of functional beta cell mass, primarily attributed to cellular demise and/or dedifferentiation. While the scientific community has devoted significant attention to unraveling beta cell dedifferentiation in type 2 diabetes, its significance in type 1 diabetes remains relatively unexplored. This perspective article critically analyzes the existing evidence for beta cell dedifferentiation in type 1 diabetes, emphasizing its potential to reduce beta cell autoimmunity. Drawing from recent advancements in both human studies and animal models, we present beta cell identity as a promising target for managing type 1 diabetes. We posit that a better understanding of the mechanisms of beta cell dedifferentiation in type 1 diabetes is key to pioneering interventions that balance beta cell function and immunogenicity.

Global ischemia has been shown to induce cardiac regenerative response in animal models. One of the suggested mechanisms behind cardiac regeneration is dedifferentiation of cardiomyocytes. How human adult cardiomyocytes respond to global ischemia is not fully known. In this study, biopsies from the left ventricle (LV) and the atrioventricular junction (AVj), a potential stem cell niche, were collected from multi-organ donors with cardiac arrest (N = 15) or without cardiac arrest (N = 6). Using immunohistochemistry, we investigated the expression of biomarkers associated with stem cells during cardiomyogenesis; MDR1, SSEA4, NKX2.5, and WT1, proliferation markers PCNA and Ki67, and hypoxia responsive factor HIF1α. The myocyte nuclei marker PCM1 and cardiac Troponin T were also included. We found expression of cardiac stem cell markers in a subpopulation of LV cardiomyocytes in the cardiac arrest group. The same cells showed a low expression of Troponin T indicating remodeling of cardiomyocytes. No such expression was found in cardiomyocytes from the control group. Stem cell biomarker expression in AVj was more pronounced in the cardiac arrest group. Furthermore, co-expression of PCNA and Ki67 with PCM1 was only found in the cardiac arrest group in the AVj. Our results indicate that a subpopulation of human cardiomyocytes in the LV undergo partial dedifferentiation upon global ischemia and may be involved in the cardiac regenerative response together with immature cardiomyocytes in the AVj.

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Actin is a central mediator of the chondrocyte phenotype. Monolayer expansion of articular chondrocytes on tissue culture polystyrene, for cell-based repair therapies, leads to chondrocyte dedifferentiation. During dedifferentiation, chondrocytes spread and filamentous (F-)actin reorganizes from a cortical to a stress fiber arrangement causing a reduction in cartilage matrix expression and an increase in fibroblastic matrix and contractile molecule expression. While the downstream mechanisms regulating chondrocyte molecular expression by alterations in F-actin organization have become elucidated, the critical upstream regulators of F-actin networks in chondrocytes are not completely known. Tropomyosin (TPM) and the RhoGTPases are known regulators of F-actin networks. The main purpose of this study is to elucidate the regulation of passaged chondrocyte F-actin stress fiber networks and cell phenotype by the specific TPM, TPM3.1, and the RhoGTPase, CDC42. Our results demonstrated that TPM3.1 associates with cortical F-actin and stress fiber F-actin in primary and passaged chondrocytes, respectively. In passaged cells, we found that pharmacological TPM3.1 inhibition or siRNA knockdown causes F-actin reorganization from stress fibers back to cortical F-actin and causes an increase in G/F-actin. CDC42 inhibition also causes formation of cortical F-actin. However, pharmacological CDC42 inhibition, but not TPM3.1 inhibition, leads to the re-association of TPM3.1 with cortical F-actin. Both TPM3.1 and CDC42 inhibition, as well as TPM3.1 knockdown, reduces nuclear localization of myocardin related transcription factor, which suppresses dedifferentiated molecule expression. We confirmed that TPM3.1 or CDC42 inhibition partially redifferentiates passaged cells by reducing fibroblast matrix and contractile expression, and increasing chondrogenic SOX9 expression. A further understanding on the regulation of F-actin in passaged cells may lead into new insights to stimulate cartilage matrix expression in cells for regenerative therapies.

OBJECTIVE: Our work is to establish more distinct association between specific stress and vascular smooth muscle cells (VSMCs) phenotypes to alleviate atherosclerotic plaque burden and delay atherosclerosis (AS) progression.
RESULTS: In recent years, VSMCs phenotypic transition has received significant interests. Different stresses were found to be associated with VSMCs phenotypic transition. However, the explicit correlation between VSMCs phenotype and specific stress has not been elucidated clearly yet. We discover that VSMCs phenotypic transition, which is widely involved in the progression of AS, is associated with specific stress. We discuss approaches targeting stresses to intervene VSMCs phenotypic transition, which may contribute to develop innovative therapies for AS.

BACKGROUND: Tissue engineering is increasingly viewed as a promising avenue for functional cartilage reconstruction. However, chondrocyte dedifferentiation during in vitro culture remains an obstacle for clinical translation of tissue engineered cartilage. Re-differentiated induction have been employed to induce dedifferentiated chondrocytes back to their original phenotype. Regrettably, these strategies have been proven to be only moderately effective.
METHODS: To explore underlying mechanism, RNA transcriptome sequencing was conducted on primary chondrocytes (P0), dedifferentiated chondrocytes (P5), and redifferentiated chondrocytes (redifferentiation-induction of P5, P5.R). Based on multiple bioinformatics analysis, LGR5 was identified as a target gene. Subsequently, stable cell lines with LGR5 knocking-down and overexpression were established using P0 chondrocytes. The phenotypic changes in P1 and P5 chondrocytes with either LGR5 knockdown or overexpression were assessed to ascertain the potential influence of LGR5 dysregulation on chondrocyte phenotypes. Regulatory mechanism was then investigated using bioinformatic analysis, protein-protein docking, immunofluorescence co-localization and immunoprecipitation.
RESULTS: The current study found that dysregulation of LGR5 can significantly impact the dedifferentiated phenotypes of chondrocytes (P5). Upregulation of LGR5 appears to activate the PI3K/AKT signal via increasing the phosphorylation levels of AKT (p-AKT1). Moreover, the increase of p-AKT1 may stabilize β-catenin and enhance the intensity of Wnt/β-catenin signal, and help to restore the dedifferentated phenotype of chondrocytes.
CONCLUSIONS: LGR5 can modulate the phenotypes of chondrocytes in P5 passage through PI3K/AKT signaling pathway.

Inheritance of acquired characteristics is the once widely accepted idea that multiple modifications acquired by an organism during its life, can be inherited by the offspring. This belief is at least as old as Hippocrates and became popular in early 19th century, leading Lamarck to suggest his theory of evolution. Charles Darwin, along with other thinkers of the time attempted to explain the mechanism of acquired traits\' inheritance by proposing the theory of pangenesis. While later this and similar theories were rejected because of the lack of hard evidence, the studies aimed at revealing the mechanism by which somatic information can be passed to germ cells have continued up to the present. In this paper, we present a new theory and provide supporting literature to explain this phenomenon. We hypothesize existence of pluripotent adult stem cells that can serve as collectors and carriers of new epigenetic traits by entering different developmentally active organ/tissue compartments through blood circulation and acquiring new epigenetic marks though cycles of differentiation/dedifferentiation or transdifferentiation. During gametogenesis, these epigenetically modified cells are attracted by gonads, transdifferentiate into germ cells, and pass the acquired epigenetic modifications collected from the entire body\'s somatic cells to the offspring.

Stem cells (SCs) undergo asymmetric division, producing transit-amplifying cells (TACs) with increased proliferative potential that move into tissues and ultimately differentiate into a specialized cell type. Thus, TACs represent an intermediary state between stem cells and differentiated cells. In the cornea, a population of stem cells resides in the limbal region, named the limbal epithelial stem cells (LESCs). As LESCs proliferate, they generate TACs that move centripetally into the cornea and differentiate into corneal epithelial cells. Upon limbal injury, research suggests a population of progenitor-like cells that exists within the cornea can move centrifugally into the limbus, where they dedifferentiate into LESCs. Herein, we summarize recent advances made in understanding the mechanism that governs the differentiation of LESCs into TACs, and thereafter, into corneal epithelial cells. We also outline the evidence in support of the existence of progenitor-like cells in the cornea and whether TACs could represent a population of cells with progenitor-like capabilities within the cornea. Furthermore, to gain further insights into the dynamics of TACs in the cornea, we outline the most recent findings in other organ systems that support the hypothesis that TACs can dedifferentiate into SCs.