Cells Therapy (Poland)

Why eukaryotic genomes are universally divided among multiple chromosomes remains an unresolved question. Although yeast and mouse cells can tolerate chromosomal fusions without impairing viability, we show here that chromosome length in mammalian cells is constrained by a biophysical limit governed by spindle geometry. Using engineered mouse cells carrying fused chromosomes of defined sizes, we identify ~308 Mb as the maximal length tolerated for faithful mitosis. Chromosomes exceeding this threshold disrupt segregation, leading to daughter cell re-coalescence and polyploidization. Aurora B kinase regulates this process by modulating spindle elongation; its inhibition induces mitotic failure even in chromosome configurations within the tolerated threshold of ~308 Mb. These findings explain the structural basis for genome fragmentation in animals and reveal a general mechanism linking chromosome size, spindle dynamics, and genome stability.

Background/Objectives: Systemic sclerosis (SSc) is a rare and severe autoimmune disease with limited treatment options. Autologous hematopoietic stem cell transplantation (HSCT) and mesenchymal stem cell transplantation (MSCT) have emerged as promising therapeutic strategies, especially for patients with refractory or rapidly progressive forms of the disease. However, no comparative synthesis has yet evaluated the clinical outcomes, safety, and applicability of these two distinct stem-cell-based interventions. This systematic review aimed to perform a comparative qualitative synthesis of clinical outcomes, safety profiles, and evidence quality for HSCT and MSCT in patients with systemic sclerosis, focusing on survival, skin fibrosis, pulmonary function, and adverse events. Methods: A comprehensive search was conducted in PubMed, ScienceDirect, Cochrane Library, and Google Scholar for the period between 2015 and May 2025. Studies were included if they reported on adult patients with a confirmed diagnosis of SSc treated with either autologous HSCT or MSCT and provided clinical outcome data. Risk of bias was assessed using the Newcastle-Ottawa Scale. Due to heterogeneity across studies, results were synthesized qualitatively. Results: Eleven studies met the inclusion criteria, comprising 504 patients (316 HSCT, 188 MSCT). HSCT showed consistent improvement in survival (1-, 5-, and 10-year), reduction in modified Rodnan skin scores (mRSS), and s ilization or improvement in pulmonary function (DLCO, FVC), albeit with a higher incidence of serious adverse events, including transplant-related mortality (up to 10%) and infectious complications. MSCT demonstrated favorable effects on skin fibrosis and lung involvement with a significantly lower toxicity profile. However, long-term survival data and methodological robustness were limited were more limited. HSCT was supported by multiple randomized controlled trials and international guidelines, while MSCT remains under clinical investigation with promising but still preliminary evidence. Conclusions: Both HSCT and MSCT demonstrate potential clinical benefits in systemic sclerosis, but they differ substantially in evidence strength and risk profiles. HSCT provides the most robust evidence for long-term disease modification in carefully selected patients, whereas MSCT represents a promising and safer investigational option, particularly for patients ineligible for intensive therapy. Further well-designed comparative studies are required to define their optimal clinical roles.

Motor neuron (MN) diversity is essential for producing the broad repertoire of animal movements, yet the molecular mechanisms that specify MN subtypes remain incompletely defined. Here, we investigate how Hox genes and their PBX cofactors shape cholinergic MN subtype identity along the anterior–posterior (A–P) axis of the C. elegans ventral nerve cord (VNC). In anterior MNs, we show that the anterior Hox genes ceh-13 (Lab/Hox1) and lin-39 (Scr/Dfd/Hox4–5) collaborate with the Hox cofactor ceh-20 (Exd/Pbx1–4) and the terminal selector unc-3 (Collier/Ebf1–4) to activate terminal identity genes. In posterior nerve cord MNs, the mid-body Hox gene mab-5 (Antp/Hox6–8) represses terminal identity gene expression by antagonizing unc-3 in a ceh-20-dependent manner. Notably, mab-5 and ceh-20 are required not only during early development but also in later life stages to maintain posterior MN identity. In lumbar MNs, the posterior Hox gene egl-5 (Abd-A/Abd-B/Hox9–13) collaborates with unc-3 to activate lumbar-specific MN terminal identity genes in a ceh-20-independent manner. We further find that ceh-20 is necessary for Hox gene expression (ceh-13, lin-39, mab-5) in VNC MNs, supporting a model where Hox positive autoregulation requires PBX activity. Together, these findings reveal PBX-dependent and independent roles for Hox genes in establishing and maintaining MN identity, illustrating how combinatorial interactions between Hox factors and terminal selectors generate neuronal subtype diversity.

Lysine lactylation (Kla) is a recently discovered post‑translational modification in which a lactyl moiety is transferred onto the ε‑amino group of lysine residues, linking cellular metabolism to epigenetic and signaling pathways. This process is regulated by a range of enzymes and metabolites, including lactate, “lactyltransferases (writers)”, “Delactylases (erasers)”, and “readers” involved in the modification. Histone lactylation has been observed in H2A, H2B, H3, and H4, with H3K18la and H4K12la being the most extensively studied sites, linked to numerous biological functions. Beyond chromatin, Kla has also been identified in a growing number of non-histone proteins, further expanding its functional significance. For instance, non-histone proteins such as AARS1-K120la, ACSS2-Kla, MRE11-K673la, NBS1-K388la and GNAT13-Kla has illuminated novel regulatory mechanisms and reinforced the potential of non-histone Kla as a promising avenue for research. Importantly, aberrant Kla patterns have been linked to various disease states, including cancer, inflammation, and metabolic disorders, highlighting its emerging potential as a biomarker and therapeutic target. In this review, we systematically summarize the molecular mechanisms, biological functions, disease associations, and therapeutic implications of both histone and non-histone Kla. By integrating current findings and discussing existing challenges, we aim to provide a comprehensive overview that will deepen understanding of Kla biology and inspire future research into its diagnostic and therapeutic potential.

Abnormal embryonic development leads to the formation of cleft palate (CP) which is difficult to be detected by genetic screening and needs sequent treatment from infants to adults. There are no interceptive treatment about CP until now. Germline deletion of phosphatase and tensin homolog (Pten) was related to embryonic malformation and regulated tumor cell proliferation through glycolysis. However, the role of Pten in CP and the relationship between CP, Pten, and glycolysis are unknown. In our research, we constructed Pten knockdown models in vitro and in vivo. Our results provided preliminary evidence that blocking Pten by its inhibitor such as VO-OHpic might be an effective interceptive treatment in early period of palate development when pregnant mother expose in harmful environment during the early period of palate development to reducing CP occurring which was related with the crosstalk between Pten, and glycolysis in the process.Graphical

Senescent chondrocytes, which are increased in osteoarthritic (OA) cartilage, promote cartilage defects and the senescent knee microenvironment by inducing senescence to surrounding normal chondrocytes by secreting senescence-associated secretory proteins. Many studies have used mesenchymal stem cells (MSCs) to treat OA, but MSC treatment remains challenging for clinical application owing to MSC quality control, engraftment, and fibrocartilage regeneration. Here, rather than relying on the direct regeneration of MSCs, we present a novel strategy to suppress OA by MSC-mediated senescent chondrocyte targeting via the paracrine activity of MSCs, thereby improving the knee microenvironment. First, to enable quality control of umbilical cord MSCs, priming MSCs by supplementing human platelet lysate (hPL) greatly enhanced MSC functions by increasing cellular glutathione levels throughout serial passaging. Intra-articular injection of primed MSCs successfully suppressed OA progression and senescent chondrocyte accumulation without direct regeneration. Indirect coculture with primed MSCs using transwell ameliorated the senescence phenotypes in OA chondrocytes, suggesting paracrine rejuvenation. Based on secretome analysis, we identified insulin-like growth factor 2 (IGF2) as a key component that induces paracrine rejuvenation by primed MSCs. The rejuvenation effects of IGF2 act through autophagy activation through the up-regulation of autophagy-related gene expression and autophagic flux. To cross-validate the effects of secreted IGF2 invivo, knockdown of IGF2 in primed MSCs substantially abolished its therapeutic efficacy in a rabbit OA model. Collectively, these findings demonstrate that hPL supplementation enables MSC quality control by increasing MSC glutathione levels. The therapeutic mechanism of primed MSCs was secreted IGF2, which induces paracrine rejuvenation of senescent OA chondrocytes by activating autophagy.

Primary Sjögren syndrome (pSS) is a systemic autoimmune disease that is characterized by the infiltration of immune cells into the salivary glands. The re-establishment of salivary glands (SGs) function in pSS remains a clinical challenge. Myeloid-derived growth factor (MYDGF) has anti-inflammatory, immunomodulatory, and tissue-functional restorative abilities. However, its potential to restore SGs function during pSS has not yet been investigated. Nonobese diabetic (NOD)/LtJ mice (pSS model) were intravenously administered with adeno-associated viruses carrying MYDGF at 11 weeks of age. Salivary flow rates were determined before and after treatment. Mice were killed 5 weeks after MYDGF treatment, and submandibular glands were collected for analyses of histological disease scores, inflammatory cell infiltration, PCR determination of genes, and Western blotting of functional proteins. Furthermore, mRNA sequencing and bioinformatics were used to predict the mechanism underlying the therapeutic effect of MYDGF. Treatment of NOD/LtJ mice with MYDGF alleviated pSS, as indicated by increased salivary flow rate, reduced lymphocyte infiltration, attenuated glandular inflammation, and enhanced AQP5 and NKCC1 expression. The gene expression levels of cytokines and chemokines, including Ccl12, Ccl3, Il1r1, Ccr2, Cx3cr1, Il7, Mmp2, Mmp14, Il1b, and Il7, significantly decreased after treatment with MYDGF, as determined by RNA sequencing. Meanwhile, MYDGF inhibits infiltration of macrophages (Mϕ) in SGs, induces polarization of M2ϕ, and suppresses C-X3C motif ligand 1 (CX3CL1)/C-X3C motif receptor 1 (CX3CR1) axis. Our findings showed that MYDGF could revitalize the SGs function of pSS, inhibit infiltration of Mϕ, and promote M2ϕ polarization via suppression of the CX3CL1/CX3CR1 axis, which has implications for potential therapy for pSS.