Commitment of human mesenchymal stromal cells to skeletal lineages is independent of their morphogenetic capacity

BACKGROUND Mesenchymal stromal cells(MSCs)are multipotent cell populations obtained from fetal and adult tissues.They share some characteristics with limb bud mesodermal cells such as differentiation potential into osteogenic,chondrogenic,and tenogenic lineages and an embryonic mesodermal origin.Although MSCs differentiate into skeletal-related lineages in vitro,they have not been shown to selforganize into complex skeletal structures or connective tissues,as in the limb.In this work,we demonstrate that the expression of molecular markers to commit MSCs to skeletal lineages is not sufficient to generate skeletal elements in vivo.AIM To evaluate the potential of MSCs to differentiate into skeletal lineages and generate complex skeletal structures using the recombinant limb(RL)system.METHODS We used the experimental system of RLs from dissociated-reaggregated human placenta(PL)and umbilical cord blood(UCB)MSCs.After being harvested and reaggregated in a pellet,cultured cells were introduced into an ectodermal cover obtained from an early chicken limb bud.Next,this filled ectoderm was grafted into the back of a donor chick embryo.Under these conditions,the cells received and responded to the ectoderm’s embryonic signals in a spatiotemporal manner to differentiate and pattern into skeletal elements.Their response to differentiation and morphogenetic signals was evaluated by quantitative poly-merase chain reaction,histology,immunofluorescence,scanning electron microscopy,and in situ hybridization.RESULTS We found that human PL-MSCs and UCB-MSCs constituting the RLs expressed chondrogenic,osteogenic,and tenogenic molecular markers while differentially committing into limb lineages but could not generate complex structures in vivo.MSCs-RL from PL or UCB were committed early to chondrogenic lineage.Nevertheless,the UCB-RL osteogenic commitment was favored,although preferentially to a tenogenic cell fate.These findings suggest that the commitment of MSCs to differentiate into skeletal lineages differs according to the source and is independent of their capacity to generate skeletal elements or connective tissue in vivo.Our results suggest that the failure to form skeletal structures may be due to the intrinsic characteristics of MSCs.Thus,it is necessary to thoroughly evaluate the biological aspects of MSCs and how they respond to morphogenetic signals in an in vivo context.CONCLUSION PL-MSCs and UCB-MSCs express molecular markers of differentiation into skeletal lineages,but they are not sufficient to generate complex skeletal structures in vivo.

The impact of maternal immune activation on the morphology and electrophysiological properties of postnatally-born neurons in the offspring

Pregnancy comes with a combination of physical changes and physiological immunosuppression that increases the susceptibility of women to pathogens and in turn,rises the prevalence of infectious diseases.

The detrimental effects of lipopolysaccharideinduced neuroinflammation on adult hippocampal neurogenesis depend on the duration of the pro-inflammatory response

Adult hippocampal neurogenesis is a finely tuned process regulated by extrinsic factors. Neuroinflammation is a hallmark of several pathological conditions underlying dysregulation of neurogenesis. In animal models, lipopolysaccharide(LPS)-induced neuroinflammation leads to a neurogenic decrease mainly associated to the early inflammatory response. However, it is not well understood how the neuroinflammatory response progresses over time and if neurogenesis continues to be diminished during the late neuroinflammatory response. Moreover, it is unknown if repeated intermittent administration of LPS along time induces a greater reduction in neurogenesis. We administered one single intraperitoneal injection of LPS or saline or four repeated injections(one per week) of LPS or saline to young-adult mice. A cohort of new cells was labeled with three 5-bromo-2-deoxyuridine injections(one per day) 4 days after the last LPS injection. We evaluated systemic and neuroinflammation-associated parameters and compared the effects of the late neuroinflammatory response on neurogenesis induced by each protocol. Our results show that 1) a single LPS injection leads to a late pro-inflammatory response characterized by microglial activation, moderate astrocytic reaction and increased interleukin-6 levels. This response correlates in time with decreased neurogenesis and 2) a repeated intermittent injection of LPS does not elicit a late pro-inflammatory response although activated microglia persists. The latter profile is not accompanied by a continued longterm hippocampal neurogenic decrease. Hereby, we provide evidence that the neuroinflammatory response is a dynamic process that progresses in a milieu-dependent manner and does not necessarily lead to a neurogenic decrease, highlighting the complex interaction between the immune system and neurogenesis.

Control of tendon cell fate in the embryonic limb: A molecular perspective

The molecular cascade underlying tendon formation starts when progenitor cells begin to express the Scleraxis(Scx)gene.Scx knockout mice develop some but not all tendons,suggesting that additional factors are necessary for tendon commitment,maintenance,and differentiation.Other transcription factors,such as Mohawk(Mkx)or early growth response(Egr),maintain Scx expression and extracellular matrix formation during fibrillogenesis.The inhibition of wingless and int-related protein signaling is necessary and sufficient to induce the expression of Scx.Once the commitment of tenogenic lineage occurs,transforming growth factor-beta(TGFβ)induces the Scx gene expression,becoming involved in the maintenance of tendon cell fate.From this point of view,we discussed two phases of the tenogenic process during limb development:dependent and independent of mechanical forces.Finally,we highlight the importance of understanding embryonic tendon development to improve therapeutic strategies in regenerative medicines for tendons.

胆固醇介导的星形胶质细胞活化与淀粉样前体蛋白表达升高和进展相关

胆固醇对于保持脂筏的完整性起必要作用,其被认为是阿尔茨海默病(AD)中淀粉样蛋白生成的关键调节因子。大多数关于淀粉样前体蛋白(APP)代谢和β淀粉样蛋白(Aβ)生成的研究都聚焦于神经元。虽然在大多数AD患者和AD转基因模型脑内发现活化的星形胶质细胞,但星形胶质细胞在AD中的作用尚未得到充分探索。在神经元Aβ生成中胆固醇的作用已得到充分研究,并归因于APP代谢中脂筏的参与。因此,本研究分析星形胶质细胞中胆固醇的作用,以及APP的表达和进展。本研究发现,胆固醇的表达导致星形胶质细胞活化,提高APP水平,增强APP和BACE-1的交互作用。这些作用与星形胶质细胞细胞膜的神经节苷脂GM1-胆固醇斑块和增高的ROS相关。

Do new neurons contribute to functional reorganization after brain damage?

The finding that adult neurogenesis occurs constitutively in the brain was a breakthrough in neuroscience and soon gained attention as a possible mechanism for neurorepair after brain damage. In a recent study we show that the dentate gyrus （DG） reorganizes anatomically over neurons undergo maturation time after damage, while new and activate in response to a contextual fear memory recall （Aguilar-Arredondo and Zepeda, 2018）. These findings provide new evidence on the possible role of neurogenesis in cognitive recovery after brain injury.