Autologous hematopoietic cell transplantation (ASCT) is a reasonable consolidation therapy for eligible patients with chemosensitive relapsed central nervous system lymphoma (CNSL) who have achieved complete remission (CR) and maintained the CR. Chimeric antigen receptor T-cell (CAR-T) therapy is an effective treatment option for patients with relapsed CNSL, although evidence on outcomes in patients who achieve CR is limited.

Muscle Stem Cells (MuSCs) drive muscle regeneration and slow pathological progression of muscle diseases. In preclinical models, nicotinamide (NAM) and pyridoxine (PN) synergistically increased MuSC proliferation and differentiation, and accelerated muscle regeneration. Herein we tested if NAM/PN could enhance MuSC activity and muscle regeneration in a randomized, placebo-controlled clinical trial. Men aged 18-49 years were supplemented daily with 714 mg NAM and 19 mg PN, or placebo, for 9 days following one session of damaging unilateral eccentric muscle contractions. The primary endpoint was MuSC activity via immunohistofluorescence on biopsy sections from the vastus lateralis muscle. Histological markers of muscle regeneration constituted secondary outcomes, and muscle damage was validated with clinical markers. 39 out of 43 enrolled participants completed the study. Supplementation of NAM/PN was well tolerated and increased blood concentrations of NAM and PN vitamers. 8 days after the contraction protocol, the number of Pax7, MyoD, and myogenin positive cells per damaged fiber was significantly higher in NAM/PN vs placebo groups (+29%-67%). NAM/PN also increased the proportion of regenerating fibers (+37%). Daily oral NAM/PN supplementation after high intensity muscle contractions enhances MuSC activity and accelerates muscle regeneration and repair, providing new opportunities for therapeutic applications in muscle recovery and muscle wasting disorders.

Renal fibrosis (RF) is a pivotal pathological feature in the progression of chronic kidney disease (CKD), yet its underlying mechanisms remain incompletely elucidated. Urine-derived stem cells (USCs) exhibit significant potential in tissue repair due to their robust paracrine function. This study aimed to investigate whether miRNAs derived from USC-derived exosomes (USC-Exos) can inhibit RF and to elucidate the underlying molecular mechanisms. Based on preliminary research, miR-26a-5p was identified as a key regulatory molecule through miRNA high-throughput sequencing of USC-Exos. Integrative transcriptomic and single-cell sequencing analyses revealed the expression characteristics and functional networks of its potential target gene, Nras, during the RF process. Subsequently, dual-luciferase reporter gene assays confirmed that miR-26a-5p directly targets NRAS and negatively regulates its expression, thereby inhibiting fibroblast proliferation, migration, and the expression of fibrotic markers α-SMA and Collagen I. Further mechanistic studies demonstrated that miR-26a-5p also suppresses the activation of the MAPK signaling pathway and mechanical signaling molecules (including PTK2, SRC, RHOA, and ROCK1), reduces nuclear translocation of YAP protein, and inhibits F-actin polymerization. Animal experiments confirmed that exosome-delivered miR-26a-5p significantly attenuates renal histopathological damage, reduces collagen deposition, and downregulates the expression of various fibrosis-related molecules. This study elucidates that miR-26a-5p from USC-Exos alleviates RF progression by targeting NRAS, inhibiting the MAPK signaling pathway, and suppressing mechanical microenvironment activation, providing a potential novel strategy for clinical treatment.

The differentiation of human embryonic stem cells (hESCs) into primordial germ cell-like cells (PGC-LCs) provides a robust in vitro model to study human germline specification. Here, we present a simple, reproducible, and cost-effective protocol for generating DEAD-box helicase 4 (DDX4)/VASA and Deleted in Azoospermia-Like (DAZL)-positive PGC-LCs from hESCs using a combination of bone morphogenetic protein 4 (BMP4) and conditioned medium (CM) derived from Stage-Specific Embryonic Antigen-4 (SSEA4)-positive human amniotic fluid stem cells (hAFSC-4). Importantly, unlike conventional protocols that rely on embryoid body formation, our method employs adherent cultures for germ cell differentiation. This approach enhances reproducibility by avoiding the spontaneous and stochastic variability inherent to embryoid body formation. This protocol provides a reproducible and physiologically relevant platform for studying human germ cell development in vitro.

Glioblastoma (GBM) is the most malignant primary brain tumor. The presence of glioma stem/initiating cells (GICs) is known to cause strong treatment resistance; therefore, GICs are a major target for GBM therapy, although there are no therapies targeting GICs clinically. To identify novel treatments for GBMs, we performed drug repositioning screening using GICs and identified T-type calcium channel blocker lomerizine-a migraine prophylactic drug. Lomerizine inhibited proliferation, migration, invasion, and cell cycle progression and induced apoptosis in GICs and differentiated glioma cells. Lomerizine had antitumor effects by inactivating STAT3 in all cell lines. Furthermore, lomerizine also dephosphorylated AKT and ERK only in GICs and strong tumor suppressive ability. Lomerizine also reduced tumor volume and prolonged overall survival in vivo. Based on our data from in vitro and in vivo experiments, lomerizine has potential as a novel GBM therapeutic agent targeting against both GICs and differentiated glioma cells and could benefit for GBM patients.

Although 5-aminolevulinic acid (5-ALA) has shown potential for hair growth in previous studies, the molecular mechanisms remain unclear. In this study, we investigated the combined effect of 5-ALA with ferric ammonium citrate (FAC) in human hair follicle models. At low micromolar concentrations, 5-ALA/FAC treatment increased proliferation of dermal papilla cells, keratinocytes, fibroblasts, and adipose-derived stem cells, and rapidly activated ERK and AKT signaling. This treatment also upregulated hair-inductive genes and restored their suppression by dihydrotestosterone or oxidative stress. In functional assays, 5-ALA/FAC treatment induced hair follicle-like structures in reconstituted skin and enhanced hair shaft elongation in ex vivo organ culture. These findings indicate that 5-ALA/FAC treatment stimulates human hair follicle growth and support its potential as a therapeutic candidate for hair loss.

Regenerative medicine is evolving exponentially due to the wide range of therapeutic applications of mesenchymal stromal cells (MSCs), including wound healing. Although the translation of tissue-derived primary MSCs (tMSCs) into clinical practice remains scarce despite preclinical success. The primary causes are donor-associated and batch-to-batch variations, replicative senescence, and the inability of large-scale manufacturing. Recent studies show that the induced MSCs (iMSCs) derived from reprogrammed induced pluripotent stem cells (iPSCs) offer distinct advantages over conventional tMSCs. This review aims to provide a comprehensive comparative analysis of the cellular characteristics, secretome composition (including growth factors, cytokines, and exosome cargo), regenerative capacities, and therapeutic potentials of tMSCs and iMSCs, with a specific focus on their applications in wound healing and tissue regeneration. The iMSCs surpass tMSCs by providing superior regenerative, immunomodulatory, and angiogenic benefits, along with unmatched consistency and scalability. iMSCs and their derivatives have exhibited remarkable capacities to promote angiogenesis, ECM production, re-epithelialization, tissue regeneration, and scarless wound healing in diabetic, cutaneous, mucosal, and burn wounds. These advantages position iMSCs as a next-generation cell therapy for managing both acute and chronic wounds, promising improved clinical outcomes and broader applicability.

Stem cells from human exfoliated deciduous teeth (SHED) and their derivatives have emerged as promising therapeutic agents for treating immune-mediated inflammatory diseases (IMIDs). IMIDs are characterized by dysregulated immune responses, leading to chronic inflammation and tissue damage. The current treatment landscape for IMIDs faces challenges, including the complexity of disease mechanisms and the limitations of existing therapies, which frequently fail to achieve long-term remission and are often associated with significant side effects. Consequently, there is a pressing need for innovative therapies that not only alleviate symptoms but also address the underlying immune dysfunction and promote the repair of damaged tissues. In this context, SHED and their derivatives offer a dual therapeutic advantage by harnessing both immunomodulatory and regenerative capacities. Research highlighted in this review demonstrates the therapeutic potential of SHED and their derivatives in multiple IMIDs, such as systemic lupus erythematosus, Sjögren's syndrome, multiple sclerosis, and rheumatoid arthritis. Critically, the aim of this review is not only to synthesize recent progress in SHED research for IMID treatment but also to highlight the strategic significance of innovative therapies emerging from the intersection of regenerative medicine and immunology.

Nasopharyngeal colonization by Streptococcus pneumoniae is characterized by bacterial adherence to epithelial cells, microinvasion, and innate immune activation. Previously, we have shown that two serotype 6B S pneumoniae mutant strains affecting bacterial metabolism (ΔproABC/pia and Δfhs/pia) colonize humans and mice, but in a murine disease model do not cause invasive infection.

Clinical translation of engineered exosomes, an emerging class of cell therapies, is hampered by challenges in each step of the manufacture flow, namely biogenesis, cargo loading, isolation, and storage. Here, we present a technology termed Tat-PNCAS-MIMS-MSC-Exo for manufacturing chemically engineered exosomes, with the above four steps being integrated by the use of the nanoparticle PNCAS-Tat (Tat peptide-conjugated protein-nanoparticle co-assembly supraparticle). This technology enables drastic improvements in all four steps of the manufacture flow of chemically engineered exosomes derived from mesenchymal stem cells (MSCs), a commonly-used cell type for cell therapies. The stimulation effect of exosome biogenesis by Tat peptide can be amplified by nanoparticle conjugation, a previously unknown nano-effect. The novel design of magnet setup MIMS (mobile internal magnetic separation) enables a unique capacity for scale-up of magnetic isolation, i.e., near-identical time for different scales to achieve near-complete isolation. This offers an effective solution to the long-standing problem of scale-up in applying magnetic isolation for biomanufacturing, which usually requires larger scales than bioanalytical applications. The manufacture process is robust, scalable, and economical. We conduct mechanistic studies of the nano-bio interactions, and demonstrate applications of the products in multiple disease models.

Chloroquine (CQ) and hydroxychloroquine (HCQ) inhibit autophagy and have shown promise as adjuvant anticancer agents, particularly for targeting therapy-resistant cancer stem cells (CSCs). However, their clinical utility is limited by systemic toxicity and poor tumor selectivity. Here, we report the design, synthesis, and photochemical evaluation of [7-(diethylamino)coumarin-4-yl]methyl (DEACM)-caged CQ and HCQ derivatives as visible-light-activated autophagy inhibitors. Selective caging of the aliphatic amine suppressed biological activity in the dark and enabled rapid release of the parent drugs upon illumination. The lead compound 1C displayed robust light-dependent cytotoxicity across multiple cancer cell lines and, upon photoactivation, recapitulated CQ's effects on LC3-II accumulation. In CSC-enriched tumorspheres, 1C completely abolished sphere formation only if illuminated. Ex vivo and in vivo studies confirmed that visible light penetrates tumor tissue sufficiently to activate 1C and locally release CQ within the tumor. These findings establish the first proof of concept for light-controlled autophagy inhibition and provide a blueprint for spatiotemporally confined anticancer therapies based on photopharmacological modulation of CSCs.

Glioblastoma (GBM) is the most malignant primary central nervous system tumor in adults, with strong invasiveness, high recurrence, and poor prognosis. Natural killer (NK) cells, innate immune cells that eliminate glioma stem cells without MHC matching, show promise for GBM immunotherapy, but their efficacy is limited by GBM's immunosuppressive tumor microenvironment (TME), especially via protein post-translational modifications (PTMs). This review summarizes seven key PTMs' (phosphorylation, acetylation, glycosylation, methylation, ubiquitination, SUMOylation, lactylation) dual regulation on NK cell therapy: physiological PTMs enhance NK cytotoxicity, targeting, and persistence; aberrant PTMs block NK activation, induce exhaustion, and promote GBM immune escape. It also analyzes bottlenecks (insufficient NK activity/persistence, GBM's PTM-mediated escape) and breakthroughs (PTM-targeted small molecules like TAK-981, CRISPR-edited NK cells, combination therapies). Future directions include BBB precision delivery, PTM-guided personalized therapy, and PTM crosstalk research, aiming to advance NK therapy's clinical translation for GBM.

Although studies support disrupted bone remodelling within geriatric populations, mid-life changes are understudied. To investigate this, we performed bone marrow transplantation assays using either 8- or 40-week-old mice. Micro-CT analyses of lethally irradiated 8-week-old mice transplanted with 40-week-old bone marrow exhibited increased mid-shaft femoral cortical bone mass and thickness. Intensive bone marrow regeneration mirrors hematopoietic development in that erythro-myeloid progenitors (EMPs) first expand to support blood production before definitive hematopoietic stem cell (HSC) production. We hypothesized that reduced HSC capacity of 40-week-old bone marrow and compensatory expansion of EMPs may facilitate gains in cortical bone. Flow cytometry analyses revealed greater EMP to HSC ratios when mice were reconstituted with increasing percentages of middle-aged bone marrow. To identify cell types mediating these effects, we performed comparative scRNA-Seq analyses and identified CD11B+CD36+ myeloid cells exhibiting enriched expression of bone anabolic cytokines. Elevated levels of Wnt ligands, especially Wnt6, characterized these cells. In lineage tracing assays, CD11B+CD36+ cells were donor-derived myeloid cells. In functional assays, we demonstrate that soluble factors produced by CD11B+CD36+ cells enhance osteogenesis. Moreover, CD11B/CD36/Wnt6 exquisitely mark anabolic macrophages within human bone marrow. These findings reveal a myeloid population present during midlife that enhances cortical bone.

Pancreatic adenocarcinoma (PDAC) arises from transformed pancreatic stem cells. Different stemness pathways are thought to be involved in the progression of PDAC.

Adipose tissue is increasingly recognized as an important component of the tumor microenvironment of colorectal cancer (CRC) and actively contributes to the progression of the disease. Adipose stem cells (ASCs), one of its key constituents, can interact with cancer cells and contribute to tumorigenic processes. However, there is a poor understanding of the underlying basis of ASC-mediated support in the progression of CRC.

An appropriate scaffold material is crucial for the success of tissue-engineered regenerative endodontic therapies. In this study, a porcine-derived decellularized dental pulp matrix hydrogel (pDDPM-G) was prepared and employed as the primary scaffold for in situ regeneration of the pulp-dentine complex in beagle dogs.

Haematopoiesis has long been a paradigm for understanding how human genetic variation can influence physiology in health and disease, ranging from the genetic characterization of Mendelian blood diseases to population-scale genomic studies of blood cell phenotypes and diseases. More recently, advances in single-cell genomics and variant-to-function mapping are enabling mechanistic insights into how genetic variation shapes blood cell development. Alongside inherited variation, the characterization of somatic mutations accumulating in haematopoietic stem cells during the lifespan has revealed clonal haematopoiesis as a ubiquitous evolutionary process, with heterogeneous clonal expansions impacting haematopoietic function and disease risk. Insights from genetic studies of haematopoiesis are translating into therapeutic applications, transforming treatment for monogenic blood disorders and promising broader applications. As methods continue to advance, haematopoiesis will remain central to understanding how genetic variation influences human biology, disease susceptibility and therapeutic response.

Enhanced P-TEFb activity is thought to promote cell proliferation by increasing the transcriptional output of RNA polymerase II. The 7SK snRNP complex, which contains LARP7 and HEXIM1, sequesters and inhibits most cellular P-TEFb to prevent premature transcription elongation. Paradoxically, instead of exerting overgrowth effects, biallelic inactivation of LARP7 is linked to Alazami syndrome, a human neurodevelopmental disorder characterized by growth restriction and cognitive impairment. Here, we report that conditional ablation of either Larp7 or Hexim1 in the murine brain reduces the size and impairs the function of the hippocampal dentate gyrus during the neonatal period. Functional analyses reveal that increased P-TEFb activity enhances self-renewal transcriptional programs in transit-amplifying neuronal progenitor cells to limit neurogenesis in developing dentate gyri. These results demonstrate that dysregulated subtissular stem cell dynamics can reconcile increased P-TEFb activity with reduced organ growth, and suggest a translational opportunity for repurposing P-TEFb inhibitors to treat medical conditions affecting dentate gyrus size and function.