Spatiotemporal multi-omics: exploring molecular landscapes in aging and regenerative medicine.

Aging and regeneration represent complex biological phenomena that have long captivated the scientific community. To fully comprehend these processes, it is essential to investigate molecular dynamics through a lens that encompasses both spatial and temporal dimensions. Conventional omics methodologies, such as genomics and transcriptomics, have been instrumental in identifying critical molecular facets of aging and regeneration. However, these methods are somewhat limited, constrained by their spatial resolution and their lack of capacity to dynamically represent tissue alterations. The advent of emerging spatiotemporal multi-omics approaches, encompassing transcriptomics, proteomics, metabolomics, and epigenomics, furnishes comprehensive insights into these intricate molecular dynamics. These sophisticated techniques facilitate accurate delineation of molecular patterns across an array of cells, tissues, and organs, thereby offering an in-depth understanding of the fundamental mechanisms at play. This review meticulously examines the significance of spatiotemporal multi-omics in the realms of aging and regeneration research. It underscores how these methodologies augment our comprehension of molecular dynamics, cellular interactions, and signaling pathways. Initially, the review delineates the foundational principles underpinning these methods, followed by an evaluation of their recent applications within the field. The review ultimately concludes by addressing the prevailing challenges and projecting future advancements in the field. Indubitably, spatiotemporal multi-omics are instrumental in deciphering the complexities inherent in aging and regeneration, thus charting a course toward potential therapeutic innovations.

A shear-thinning, ROS-scavenging hydrogel combined with dental pulp stem cells promotes spinal cord repair by inhibiting ferroptosis.

Spinal cord injury (SCI) is a serious clinical disease. Due to the deformability and fragility of the spinal cord, overly rigid hydrogels cannot be used to treat SCI. Hence, we used TPA and Laponite to develop a hydrogel with shear-thinning ability. This hydrogel exhibits good deformation, allowing it to match the physical properties of the spinal cord; additionally, this hydrogel scavenges ROS well, allowing it to inhibit the lipid peroxidation caused by ferroptosis. According to the in vivo studies, the TPA@Laponite hydrogel could synergistically inhibit ferroptosis by improving vascular function and regulating iron metabolism. In addition, dental pulp stem cells (DPSCs) were introduced into the TPA@Laponite hydrogel to regulate the ratios of excitatory and inhibitory synapses. It was shown that this combination biomaterial effectively reduced muscle spasms and promoted recovery from SCI.

Corrigendum: Hypoxia response element-directed expression of aFGF in neural stem cells promotes the recovery of spinal cord injury and attenuates SCI-induced apoptosis.

[This corrects the article DOI: 10.3389/fcell.2021.693694.].

Catalpol as a Component of Rehmannia glutinosa Protects Spinal Cord Injury by Inhibiting Endoplasmic Reticulum Stress-Mediated Neuronal Apoptosis.

Disturbance of the internal environment in the spinal cord after spinal cord injury (SCI) is an important cause of the massive death of neurons in the injury area and one of the major problems that lead to the difficult recovery of motor function in patients. Rehmannia glutinosa, a famous traditional Chinese medicine, is commonly used in neurodegenerative diseases, whereas an iridoid glycoside extract of catalpol (CAT), with antioxidant, antiapoptotic, and neuroprotective pharmacological effects. However, the neuroprotective and anti-apoptosis mechanism of CAT in SCI remains unclear. In our study, we found that CAT has a restorative effect on the lower limb motor function of rats with SCI by establishing a rat model of SCI and treating CAT gavage for 30 days. Our study further found that CAT has the effect of inhibiting apoptosis and protecting neurons, and the action pathway may reduce endoplasmic reticulum (ER) stress by inhibiting CHOP and GRP78 expression and then reduce apoptosis and protect neurons through the Caspase3/Bax/Bcl-2 pathway. In conclusion, we demonstrated that CAT can treat SCI by inhibiting ER stress-mediated neuronal apoptosis and has the potential to be a clinical drug for the treatment of SCI.

Versatile subtypes of pericytes and their roles in spinal cord injury repair, bone development and repair.

Vascular regeneration is a challenging topic in tissue repair. As one of the important components of the neurovascular unit (NVU), pericytes play an essential role in the maintenance of the vascular network of the spinal cord. To date, subtypes of pericytes have been identified by various markers, namely the PDGFR-ß, Desmin, CD146, and NG2, each of which is involved with spinal cord injury (SCI) repair. In addition, pericytes may act as a stem cell source that is important for bone development and regeneration, whilst specific subtypes of pericyte could facilitate bone fracture and defect repair. One of the major challenges of pericyte biology is to determine the specific markers that would clearly distinguish the different subtypes of pericytes, and to develop efficient approaches to isolate and propagate pericytes. In this review, we discuss the biology and roles of pericytes, their markers for identification, and cell differentiation capacity with a focus on the potential application in the treatment of SCI and bone diseases in orthopedics.

The Prognosis and Immune Microenvironment Related Factor Interleukin-23 in Clear Cell Renal Cell Carcinoma: A Radiological Investigation.

PURPOSE: To explore the ccRCC clinical and immune characteristics correlated with IL-23 expression level and build pre-operative prediction models based on contrast CT scans. MATERIALS AND METHODS: The study included the cancer genome atlas kidney renal clear cell carcinoma cases to build a bioinformatics cohort. The cases with qualified contrast CT images were selected as radiographic and radiomics cohort. The IL-23 expression level groups were defined by median-based thresholding. The clinical characteristics were compared between groups. The impacts of IL-23 on immune microenvironment composition were measured via the CIBERSORT. Two radiologists evaluated the pre-operative contrast CT images. The radiomics features were automatically extracted. IL-23 group-specific radiographic and radiomics features were collected and used for prediction model establishment via Orange Data Mining Toolbox. P < 0.05 was set as statistically significant. RESULTS: For total, 530 ccRCC cases were included. The IL-23 group was significantly associated with survival, histologic grade, AJCC tumor stage, AJCC cancer stage, and plasma calcium level. Except for Treg and other T cells, IL-23 showed correlation with NK cell, mast cell, monocyte infiltration. Axial length was the only significant radiographic measurement between IL-23 groups. The radiomics features established an IL-23 group prediction model with the highest 10-fold cross-verification AUC of 0.842. CONCLUSION: The clear cell renal cell carcinoma IL-23 expression level had prognosis and immune microenvironment correlation and could be predicted by pre-operative radiomics features.

Notoginseng Triterpenes Inhibited Autophagy in Random Flaps via the Beclin-1/VPS34/LC3 Signaling Pathway to Improve Tissue Survival.

Random flaps are widely used in tissue reconstruction, attributed to the lack of vascular axial limitation. Nevertheless, the distal end of the flap is prone to necrosis due to the lack of blood supply. Notoginseng triterpenes (NTs) are the active components extracted from Panax notoginseng, reducing oxygen consumption and improving the body's tolerance to hypoxia. However, their role in random flap survival has not been elucidated. In this study, we used a mouse random skin flap model to verify that NT can promote cell proliferation and migration and that increasing blood perfusion can effectively improve the survival area of a skin flap. Our study also showed that the autophagy of random flaps after NT treatment was activated through the Beclin-1/VPS34/LC3 signaling pathway, and the therapeutic effect of NT significantly decreased after VPS34 IN inhibited autophagy. In conclusion, we have demonstrated that NT can significantly improve the survival rate of random flaps through the Beclin-1/VPS34/LC3 signaling pathway, suggesting that it might be a promising clinical treatment option.

Nerve growth factor (NGF) with hypoxia response elements loaded by adeno-associated virus (AAV) combined with neural stem cells improve the spinal cord injury recovery.

The ischemia and hypoxia microenvironment after spinal cord injury (SCI) makes SCI repair a challenging problem. With various stimulus, chances for neural stem cells (NSCs) to differentiate into neurons, astrocytes, oligodendrocytes are great and is considered as a potential source of the stem cell therapy to SCI. Our research used adeno-associated virus (AAV) to carry the target gene to transfect neural stem cells. Transfected NSCs can express nerve growth factor (NGF) navigated by five hypoxia-responsive elements (5HRE). Therefore, the 5HRE-NGF-NSCs could express NGF specifically in hypoxia sites to promote the tissue repair and function recovery. Based on the regeneration of neurocytes and promotion of the recovery found in SCI models, via locomotor assessment, histochemical staining and molecular examinations, our results demonstrated that 5HRE-NGF-NSCs could improve the motor function, neurons survival and molecules expression of SCI rats. Meanwhile, the downregulated expression of autophagy-related proteins indicated the inhibitive effect of 5HRE-NGF-NSCs on autophagy. Our research showed that 5HRE-NGF-NSCs contribute to SCI repair which might via inhibiting autophagy and improving the survival rate of neuronal cells. The new therapy also hampered the hyperplasia of neural glial scars and induced axon regeneration. These positive functions of 5HRE-NGF-NSCs all indicate a promising SCI treatment.

Hypoxia Response Element-Directed Expression of aFGF in Neural Stem Cells Promotes the Recovery of Spinal Cord Injury and Attenuates SCI-Induced Apoptosis.

Reducing neuronal death after spinal cord injury (SCI) is considered to be an important strategy for the renovation of SCI. Studies have shown that, as an important regulator of the development and maintenance of neural structure, acidic fibroblast growth factor (aFGF) has the role of tissue protection and is considered to be an effective drug for the treatment of SCI. Neural stem cells (NSCs) are rendered with the remarkable characteristics to self-replace and differentiate into a variety of cells, so it is promising to be used in cell transplantation therapy. Based on the facts above, our main aim of this research is to explore the role of NSCs expressing aFGF meditated by five hypoxia-responsive elements (5HRE) in the treatment of SCI by constructing AAV-5HRE-aFGF-NSCs and transplanting it into the area of SCI. Our research results showed that AAV-5HRE-aFGF-NSCs can effectively restore the motor function of rats with SCI. This was accomplished by inhibiting the expression of caspase 12/caspase 3 pathway, EIF2α-CHOP pathway, and GRP78 protein to inhibit apoptosis.

AAV2-mediated and hypoxia response element-directed expression of bFGF in neural stem cells showed therapeutic effects on spinal cord injury in rats.

Neural stem cell (NSCs) transplantation has been one of the hot topics in the repair of spinal cord injury (SCI). Fibroblast growth factor (FGF) is considered a promising nerve injury therapy after SCI. However, owing to a hostile hypoxia condition in SCI, there remains a challenging issue in implementing these tactics to repair SCI. In this report, we used adeno-associated virus 2 (AAV2), a prototype AAV used in clinical trials for human neuron disorders, basic FGF (bFGF) gene under the regulation of hypoxia response element (HRE) was constructed and transduced into NSCs to yield AAV2-5HRE-bFGF-NSCs. Our results showed that its treatment yielded temporally increased expression of bFGF in SCI, and improved scores of functional recovery after SCI compared to vehicle control (AAV2-5HRE-NSCs) based on the analyses of the inclined plane test, Basso-Beattie-Bresnahan (BBB) scale and footprint analysis. Mechanistic studies showed that AAV2-5HRE-bFGF-NSCs treatment increased the expression of neuron-specific neuronal nuclei protein (NeuN), neuromodulin GAP43, and neurofilament protein NF200 while decreased the expression of glial fibrillary acidic protein (GFAP) as compared to the control group. Further, the expressions of autophagy-associated proteins LC3-II and Beclin 1 were decreased, whereas the expression of P62 protein was increased in AAV2-5HRE-bFGF-NSCs treatment group. Taken together, our data indicate that AAV2-5HRE-bFGF-NSCs treatment improved the recovery of SCI rats, which is accompanied by evidence of nerve regeneration, and inhibition of SCI-induced glial scar formation and cell autophagy. Thus, this study represents a step forward towards the potential use of AAV2-5HRE-bFGF-NSCs for future clinical trials of SCI repair.

Hypoxia response element-directed expression of bFGF in dental pulp stem cells improve the hypoxic environment by targeting pericytes in SCI rats.

Cell-based transplantation strategies possess great potential for spinal cord injury (SCI) repair. Basic fibroblast growth factor (bFGF) has been reported to have multiple neuro-promoting effects on developing and adult nervous system of mammals and considered a promising therapy for nerve injury following SCI. Human dental pulp stem cells (DPSCs) are abundant stem cells with low immune rejection, which can be considered for cell replacement therapy. The purpose of this study was to investigate the roles of DPSCs which express bFGF under the regulation of five hypoxia-responsive elements (5HRE) using an adeno-associated virus (AAV-5HRE-bFGF-DPSCs) in SCI repairing model. In this study, DPSCs were revealed to differentiate into CD13+ pericytes and up-regulate N-cadherin expression to promote the re-attachment of CD13+ pericytes to vascular endothelial cells. The re-attachment of CD13+ pericytes to vascular endothelial cells subsequently increased the flow rate of blood in microvessels via the contraction of protuberance. As a result, increased numbers of red blood cells carried more oxygen to the damaged area and the local hypoxia microenvironment in SCI was improved. Thus, this study represents a step forward towards the potential use of AAV-5HRE-bFGF-DPSCs in SCI treatment in clinic.

Gelatine nanostructured lipid carrier encapsulated FGF15 inhibits autophagy and improves recovery in spinal cord injury.

Gelatine nanostructured lipid carriers (GNLs) have attracted increasing attention due to their biodegradable status and capacity to capture various biologically active compounds. Many studies demonstrated that fibroblast growth factor therapies after spinal cord injury (SCI) can be used in the future for the recovery of neurons. In this study, the therapeutic effects of GNL-encapsulated fibroblast growth factor 15 (FGF15) and FGF15 were compared in SCI. The FGF15-GNLs had 88.17 ± 1.22% encapsulation efficiency and 4.82 ± 0.12% loading capacity. The effects of FGF15-GNLs and FGF15 were assessed based on the Basso-Beattie-Bresnahan (BBB) locomotion scale, inclined plane test and footprint analysis. Immunofluorescent staining was used to identify the expression of autophagy-associated proteins, GFAP (glial fibrillary acidic protein) and neurofilament 200 (NF200). FGF15-GNLs use enhanced the repair after SCI compared to the effect of FGF15. The suppression of autophagy-associated proteins LC3-II and beclin-1, and p62 enhancement by FGF15-GNLs treatment were more pronounced. Thus, the effects of FGF15-GNLs on the recovery after SCI are related to the inhibition of autophagy and glial scar, and promotion of nerve regeneration in SCI.

Fibroblast Growth Factor 22 Inhibits ER Stress-Induced Apoptosis and Improves Recovery of Spinal Cord Injury.

Currently, inhibiting or reducing neuronal cell death is the main strategy to improve recovery of spinal cord injury (SCI). Therapies using nerve growth factors to treat SCI mainly focused on reducing the area damaged by postinjury degeneration to promote functional recovery. In this report, we investigated the mechanism of ER (endoplasmic reticulum) stress-induced apoptosis and the protective action of fibroblast growth factor 22 (FGF22) in vivo. Our results demonstrated that ER stress-induced apoptosis plays a significant role in injury of SCI model rats. FGF22 administration promoted recovery and increased neuron survival in the spinal cord lesions of model mice. The protective effect of FGF22 is related to decreased expression of CHOP (C/EBP-homologous protein), GRP78 (glucose-regulated protein 78), caspase-12, X-box binding protein 1 (XBP1), eukaryotic initiation factor 2α (Eif-2α) and Bad which are ER stress-induced apoptosis response proteins. Moreover, FGF22 administration also increased the number of neurons and the expression of growth-associated protein 43 (GAP43) which was related to axon regeneration. We also demonstrated that the protective effect of FGF22 effectively reduces neuronal apoptosis and promotes axonal regeneration. Our study first illustrated that the function of FGF22 is related to the inhibition of ER stress-induced cell death in SCI recovery via activation of downstream signals. This study also suggested a new tendency of FGF22 therapy development in central neural system injuries, which involved chronic ER stress-induced apoptosis.

Systemic Administration of Fibroblast Growth Factor 21 Improves the Recovery of Spinal Cord Injury (SCI) in Rats and Attenuates SCI-Induced Autophagy.

Protecting the death of nerve cells is an essential tactic for spinal cord injury (SCI) repair. Recent studies show that nerve growth factors can reduce the death of nerve cells and promote the healing of nerve injury. To investigate the conducive effect of fibroblast growth factor 21 (FGF21) on SCI repair. FGF21 proteins were systemically delivered into rat model of SCI via tail vein injection. We found that administration of FGF21 significantly promoted the functional recovery of SCI as assessed by BBB scale and inclined plane test, and attenuated cell death in the injured area by histopathological examination with Nissl staining. This was accompanied with increased expression of NeuN, GAP43 and NF200, and deceased expression of GFAP. Interestingly, FGF21 was found to attenuate the elevated expression level of the autophagy marker LC3-II (microtubules associated protein 1 light chain 3-II) induced by SCI in a dose-dependent manner. These data show that FGF21 promotes the functional recovery of SCI via restraining injury-induced cell autophagy, suggesting that systemic administration of FGF21 could have a therapeutic potential for SCI repair.

[Progress on neurogenesis mechanisms of endogenous adult neural stem cells].

Endogenous adult neural stem cells are closely related to the normal physiological functions of the brain and many neurodegenerative diseases. Neurons are affected by factors such as extracellular microenvironment and intracellular signaling. In recent years, some specific signaling pathways have been found that affect the occurrence of neural stem cells in adult neural networks, including proliferation, differentiation, maturation, migration, and integration with host functions. In this paper, we summarize the signals and their molecular mechanisms, including the related signaling pathways, neurotrophic factors, neurotransmitters, intracellular transcription factors and epigenetic regulation of neuronal differentiation from both the extracellular and intracellular aspects, providing basic theoretical support for the treatment of central nervous system diseases through neural stem cells approach.

Nonlocal tunnel magnetoresistance and thermal rectification effect in a nanoscale three-terminal junction.

We investigate thermally driven electronic transport through a quantum dot (QD) coupled to two ferromagnetic leads and one normal-metallic lead. The effect of spin accumulation and temperature bias on the tunnel magnetoresistance (TMR) is examined. We obtain a nonlocal negative TMR, which also exhibits a rectification effect as a function of the QD level modulated by a gate voltage. For a negative QD level, the TMR is zero, and the TMR is negative for a positive QD level. This effect arises from the interplay of the spin accumulation and thermoelectric transport, which detects the sign reversal of spin accumulation in the QD. In addition, our system can also be used as a spin current generator.

Spin-polarized transport through an Aharonov-Bohm interferometer embedded with a quantum dot molecule.

We propose an Aharonov-Bohm interferometer with a quantum dot molecule embedded in one arm and study the spin-dependent transport due to the interplay of the Fano and Rashba effects. It is found that the Fano resonances of the molecular states exhibit opposite directions of asymmetric tails with one being from peak to dip and the other from dip to peak. The Rashba spin-orbit interaction induces a spin-dependent phase, making the two Fano dips overlap for one spin component of conductance and the two Fano peaks overlap for the other spin component. Both the direction and magnitude of the spin polarization of the conductance are easily controlled and manipulated through the Rashba parameter and interdot coupling strength. In addition, spin accumulations with opposite signs can be generated in the two quantum dots.