Preface for Special Issue: Single-Cell and Spatially Resolved Omics

We are delighted to present you this special issue,which consists of a collection of articles focusing on the novel and rapidly evolving field of single-cell and spatially resolved omics.This encompasses epigenomics,transcriptomics,proteomics,and metabolomics.Recent technological advances,coupled with computational techniques,have advanced the scope of this discipline to allow the investigation of individual cells down to an unprecedented level of detail.Researchers can now explore the cellular heterogeneity and the intricate interplay among its multiple molecular elements comprehensively.This detailed exploration is instrumental not only in understanding the fundamental biology of cell functions but also identifying new therapeutic targets and strategies to tackle various disease contexts.

In this special issue,we proudly feature several comprehensive review articles that present the state-of-the-art developments in single-cell and spatially resolved omics.Fangma et al.review the cutting-edge landscape of spatially resolved multi-omics technologies,including spatial genomics,transcriptomics,proteomics,and metabolomics,highlighting key technologies,computational algorithms,and emerging applications in fields such as neuroscience by focusing on two major approaches in spatial transcriptomics and mass spectrometry imaging technologies used in spatial proteomics and spatial metabolomics.Xie and colleagues provide profound insights into the latest advancements in single-cell multiomics and spatial multi-omics.In this study,they place emphasis on the evolution and application of these emerging techniques in the context of metabolism-related diseases,including obesity,diabetes,nonalcoholic fatty liver disease,and cardiovascular disease,thereby illuminating the significant progress that has occurred in this relatively new field.

Furthermore,we also take pleasure in presenting original research articles that reflect the exciting advancements and applications of single-cell and spatially resolved omics.Sun et al.,building on the cover story,reported a groundbreaking discovery,wherein cannabidiol (CBD),a non-psychoactive natural active ingredient from the cannabis plant,was found to suppress M2-like macrophages while promoting M1-like macrophages in colorectal tumors both in strength and quantity.This was achieved through the integration of single-cell RNA sequencing (scRNAseq) and single-cell ATAC sequencing (scATAC-seq) technologies,providing novel insights into the antitumor effects of CBD.

Huang et al.delineated a novel prolific basal cell (PBC) state,solely characterized by the transcription factor CUT-like homeobox 1 (Cux1),as detected through sophisticated scRNA-seq protocols and in situ hybridization.Subsequent in vitro examinations confirmed the essentiality of Cux1 for keratinocyte proliferation,attributable to its regulation of an array of cyclindependent kinases (CDKs) and cyclins.This intricate study offers a comprehensive exploration of transcriptomic modifications within a chronic dry skin mouse model,thereby uncovering a potential therapeutic target against dry skin-related dermatoses.

Yin and colleagues,in their groundbreaking work,have illuminated the crucial interplay that occurs between Guca2b secreted by enterocytes,and the Gucy2c receptor found on the surfaces of stem,transit-amplifying cells,Paneth,and goblet cells during episodes of intestinal ischemia-reperfusion (II/R) injury in mice.Employing scRNA-seq,their findings unraveled that the mucosal barrier integrity in the intestines may be compromised by glutathioneS-transferase mu 3 (GSTM3),a unique marker implicated in modulating mitogen-activated protein kinases(MAPK)signaling amidst II/R injury.This revelation demystifies the complexity of intestinal cellular heterogeneity and the operative mechanics of GSTM3,thus paving a firmer foundation for more effective treatment strategies for II/R injury.

Moreover,Wang and colleagues presented a spatially resolved metabolomics analysis,revealing the metabolic vulnerability of choline which is highly active in various types of cancer.Then they developed a choline-modified strategy for designing small molecule-drug conjugates(SMDCs)targeted towards fooling tumor cells into indiscriminately taking in choline-modified chemotherapy drugs for precise cancer therapy.This study provides new ideas for developing SMDCs aimed at making targeted cancer therapy a reality.

Undertaking a comprehensive scRNA-seq approach,Li and team painstakingly cultivated a broad map of cell clusters in hippocampal specimens derived from both wild type (WT) mice and mice carrying 5× FAD mutations,at various life stages,i.e.,2,12,and 24 months.The essence of their work revolves around capturing the diverse immune behaviors and phenotypic attributes of microglia.The study encapsulates the dynamics of internal and external signal propagation within the microglial population,unearthing crucial aspects of neuroinflammation pathways and cell behavior interaction guided by immune response in the hippocampus.Furthermore,amyloid precursor protein (APP) and colony stimulating factor(CSF)signals seem to serve as the driving force behind the shift of 5×FAD mice from typical aging progression towards the manifestation of Alzheimer’s disease.

In an intriguing study,Shen and co-workers administered bavachin (BV) to mice over a seven-day period.Proceeding to profile gene expression within hepatocytes and nonparenchymal cells to a single-cell degree,they distinguished three distinct hepatocyte subsets in response to BV treatment.Among these subsets,one particular hepatocyte variant exhibited drastic modification of lipid metabolism.This phenotype was associated with amplified expression of apolipoproteins,carboxylesterases,and stearoyl-CoA desaturase 1(Scd1).Additionally,the researchers unveiled that an ensemble of endogenous transcription factors such as Srebf1 and Hnf4a,along with extrinsic signals from niche cells,likely wield regulatory influence over the described molecular phenomena in BV-treated hepatocytes.In summation,their research elucidates the hepatocytic adaptations in the face of BV insult,decrypts the underpinning molecular mechanisms,and proposes that Scd1 could serve as a cornerstone molecule for early prognostication of hepatotoxicity.

Chen et al.have unveiled that artesunate (ART) plays a crucial role in hampering the activation of pro-inflammatory macrophages that are recruited in the throes of sepsis,a finding derived from scRNA-seq analysis.More remarkably,ART was revealed to rejuvenate the chemotactic capabilities and immunological functions of neutrophils in the septic spleen.Moreover,it inhibited the stimulation of regulatory T cells,whilst concurrently boosting the cytotoxic activities of natural killer cells during sepsis.Further observation disclosed that ART also fostered both the differentiation and activity of splenic B cells in septic mice.Such findings postulate that ART possesses the capacity to alleviate the inflammatory and/or immunosuppressive states of various immune cells implicated in sepsis,thereby bringing about a balanced immune homeostasis within the host organism.Overall,their study yields a comprehensive exploration of the modulatory impact of ART on the microenvironment of the spleen during sepsis,thereby gesturing towards the potential utility of ART as an adjunctive therapeutic strategy in clinical sepsis management.

Overall,this special issue introduces a diverse array of cuttingedge research topics in the field of single-cell and spatially resolved omics.It illustrates the tremendous progress and potential of these techniques for uncovering novel biological insights and contributing to the development of novel therapeutics.Our sincere gratitude goes to all authors for their valuable contributions,and we hope that readers find this collection of articles as stimulating and inspiring as we do.