Stem Cell Niche,the Microenvironment and Immunological Crosstalk

The concept of stem cells, their physiological existence, the intricate anatomical localization, the known and the unknown functions, and their exclusive utility for the purpose of regenerative medicine, are all now encompassed within an emergent question, ＇how compatible these cells are immunologically？＇ Indeed, the medical aspects of stem cells are dependent on a large number of queries based on the basic properties of the cells. It has greatly been emphasized to probe into the basic research on stem cells before any successful therapeutic attempts are made. One of the intricate aspects of the adult stem cells is its immunological behavior in relation to the microenvironmental associates, the stromal cells in the presence of a suitable target. Cellular ＆ Molecular Immunology.

Precise tissue bioengineering and niches of mesenchymal stem cells:Their size and hierarchy matter

Stem cell microterritories(niches),as a specialized part of the extracellular matrix(ECM),are considered an important target and tool for the development of new materials,medical implants,and devices.However,tissue bioengineering products that have stem cell niches of known size on the surface or in the bulk structure of artificial materials are practically unknown.This brief review attempts to draw attention to the problematic aspects of niches as specific parts of the ECM,such as their hierarchy and size for mesenchymal stromal/stem cells(MSCs).These parameters arise directly from numerous definitions of stem cell niches as specialized morphological microterritories found in various tissues.The authors of this review analyze the known information on the hierarchy of MSC microterritories by analogy with that of hematopoietic stem cells.Occasional reports on the size of artificial MSC niches compared to natural niche candidates are summarized.A consensus on a hierarchy and optimal range of niche sizes for MSCs and other stem cells is needed to accelerate the development of prototyping technologies and additive manufacturing in applications to precise tissue bioengineering and regenerative medicine.

Senescent mesenchymal stem/stromal cells in pre-metastatic bone marrow of untreated advanced breast cancer patients

Breast cancer is the predominant form of carcinoma among women worldwide,with 70%of advanced patients developing bone metastases,with a high mortality rate.In this sense,the bone marrow(BM)mesenchymal stem/stromal cells(MSCs)are critical for BM/bone homeostasis,and failures in their functionality,transform the BM into a premetastatic niche(PMN).We previously found that BM-MSCs from advanced breast cancer patients(BCPs,infiltrative ductal carcinoma,stage III-B)have an abnormal profile.This work aims to study some of the metabolic and molecular mechanisms underlying MSCs shift from a normal to an abnormal profile in this group of patients.A comparative analysis was undertaken,which included self-renewal capacity,morphology,proliferation capacity,cell cycle,reactive oxygen species(ROS)levels,and senescence-associatedβ‑galactosidase(SA‑β‑gal)staining of BMderived MSCs isolated from 14 BCPs and 9 healthy volunteers(HVs).Additionally,the expression and activity of the telomerase subunit TERT,as well as telomere length,were measured.Expression levels of pluripotency,osteogenic,and osteoclastogenic genes(OCT-4,SOX-2,M-CAM,RUNX-2,BMP-2,CCL-2,M-CSF,and IL-6)were also determined.The results showed that MSCs from BCPs had reduced,self-renewal and proliferation capacity.These cells also exhibited inhibited cell cycle progression and phenotypic changes,such as an enlarged and flattened appearance.Additionally,there was an increase in ROS and senescence levels and a decrease in the functional capacity of TERT to preserve telomere length.We also found an increase in pro-inflammatory/pro-osteoclastogenic gene expression and a decrease in pluripotency gene expression.We conclude that these changes could be responsible for the abnormal functional profile that MSCs show in this group of patients.

Applications of scaffolds:Tools for enhancing the immunomodulation of mesenchymal stromal cells

Exogenously delivered mesenchymal stromal cells(MSCs)are therapeutically beneficial owing to their paracrine effect;they secrete various cytokines,nucleic acids,and proteins.Multiple bioengineering techniques can help MSC cultures to release secretomes by providing stem cell niche-like conditions(both structurally and functionally).Various scaffolds mimic the natural extracellular matrix(ECM)using both natural and synthetic polymers,providing favorable environments for MSC proliferation and differentiation.Depending on material properties,either topographically or elastically structured scaffolds can be fabricated.Three-dimensional scaffolds have tunable substrate rigidities and structures,aiding MSC cultivation.Decellularized ECM-derived hydrogels are similar to the natural ECM,thus improving the paracrine effects of MSCs.Here,we discuss recent research on the application of scaffolds to maximize the immunomodulatory function of MSCs.

角膜缘niche细胞与基质细胞维持角膜缘干细胞功能的对比研究

目的比较角膜缘niche细胞(limbal niche cells,LNCs)与角膜缘基质细胞(limbal stromal cells,LSCs)在维持角膜缘干细胞功能上的不同特性。方法将LNCs和LSCs分别从6个角膜缘组织分离,并在相同的条件下培养、传代。LNCs与LSCs经丝裂霉素C(mitomycin C,MMC)处理后分为LNCs组与LSCs组作为饲养细胞分别与角膜缘干细胞共培养,比较两组角膜缘干细胞克隆形成率(colony-forming efficiency,CFE)、上皮细胞复层化以及细胞标志物和部分基因的表达。结果LNCs组角膜缘干细胞CFE(6.57±1.54)%高于LSCs组(1.43±0.47)%。LNCs组细胞复层上皮数(4~5层)多于LSCs组(2~3层)。角膜缘干细胞克隆与免疫荧光染色及mRNA半定量分析结果显示,LNCs组比LSCs组表达了更多干细胞标志物ΔNp63,能更有效地维持角膜缘干细胞的细胞特性。逆转录PCR分析结果显示,LNCs组与LSCs组都分泌了一些维持角膜缘干细胞生长的生长因子,但LNCs组比LSCs组高表达上皮型钙黏蛋白(E-cadherin),低表达营养神经素3(NT3),能更好地支持角膜上皮增殖。结论LNCs比LSCs能更好地支持角膜缘干细胞的生长及维持其干细胞特性。

The cellular niche for intestinal stem cells: ateam effort

The rapidly self-renewing epithelium in the mammalian intestine is maintained by multipotent intestinal stem cells(ISCs) located at the bottom of the intestinal crypt that are interspersed with Paneth cells in the small intestine andPaneth-like cells in the colon. The ISC compartment is also closely associated with a sub-epithelial compartmentthat contains multiple types of mesenchymal stromal cells. With the advances in single cell and gene editingtechnologies, rapid progress has been made for the identification and characterization of the cellular componentsof the niche microenvironment that is essential for self-renewal and differentiation of ISCs. It has becomeincreasingly clear that a heterogeneous population of mesenchymal cells as well as the Paneth cells collectivelyprovide multiple secreted niche signals to promote ISC self-renewal. Here we review and summarize recentadvances in the regulation of ISCs with a main focus on the definition of niche cells that sustain ISCs.

努力开创角膜缘干细胞临床研究新局面

角膜缘干细胞(LSCs)移植是治疗化学眼烧伤、Stevens-Johnson综合征等导致的角膜缘干细胞缺乏的主要方法,也是全身干细胞移植领域临床转化最为成功的移植方法。近年来,LSCs移植取得了一系列重要的进展,但仍然存在许多问题,面临多种挑战。将来应在获取稳定种子细胞来源、寻找新的载体材料、提高干细胞扩增效率、改善基质微环境、抑制免疫排斥等方向继续努力,进一步提高LSCs的临床疗效,开创LSCs移植的新局面。

The long and winding road:homeostatic and disordered haematopoietic microenvironmental niches:a narrative review

Haematopoietic microenvironmental niches have been described as the‘gatekeepers’for the blood and immune systems.These niches change during ontogeny,with the bone marrow becoming the predominant site of haematopoiesis in post-natal life under steady state conditions.To determine the structure and function of different haematopoietic microenvironmental niches,it is essential to clearly define specific haematopoietic stem and progenitor cell subsets during ontogeny and to understand their temporal appearance and anatomical positioning.A variety of haematopoietic and non-haematopoietic cells contribute to haematopoietic stem and progenitor cell niches.The latter is reported to include endothelial cells and mesenchymal stromal cells(MSCs),skeletal stem cells and/or C-X-C motif chemokine ligand 12-abundant-reticular cell populations,which form crucial components of these microenvironments under homeostatic conditions.Dysregulation or deterioration of such cells contributes to significant clinical disorders and diseases worldwide and is associated with the ageing process.A critical appraisal of these issues and of the roles of MSC/C-X-C motif chemokine ligand 12-abundant-reticular cells and the more recently identified skeletal stem cell subsets in bone marrow haematopoietic niche function under homeostatic conditions and during ageing will form the basis of this research review.In the context of haematopoiesis,clinical translation will deal with lessons learned from the vast experience garnered from the development and use of MSC therapies to treat graft versus host disease in the context of allogeneic haematopoietic transplants,the recent application of these MSC therapies to treating emerging and severe coronavirus disease 2019(COVID-19)infections,and,given that skeletal stem cell ageing is one proposed driver for haematopoietic ageing,the potential contributions of these stem cells to haematopoiesis in healthy bone marrow and the benefits and challenges of using this knowledge for rejuvenating the age-compromised bone marrow haematopoietic niches and restoring haematopoiesis.

新型肠道间质细胞MRISC调控炎症过程中肠道干细胞的损伤修复

炎症和损伤能迅速激发肠道干细胞增殖促进组织修复再生。肠道微环境组分中的重要成员—肠道间质细胞在这个过程中起到了非常重要的调控作用。近年来,随着单细胞测序技术的快速发展,研究人员揭示了肠道间质细胞是一类异常复杂且具高度异质性的细胞群。目前,领域内对不同肠道间质细胞亚群的基因特征、空间分布、潜在功能以及调节的细胞和分子机制仍知之甚少。该文总结了该团队发现肠道间质细胞新亚群MRISC(MAP3K2-regulated intestinal stromal cell)的过程,并详细描述了MRISC在肠道炎症和损伤过程中通过特异调控肠道干细胞微环境的R-spondin1-Wnt信号参与肠道上皮组织损伤修复的作用和机理,为MAPK信号在肠道疾病研究和治疗中的应用提供了新思路。