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Application of rapamycin or tumor necrosis factor alpha in preventing and/or treating diseases associated with mesenchymal stem cell injury

A mesenchymal stem cell, rapamycin technology, applied in the prevention and/or treatment of diseases related to mesenchymal stem cell damage, rapamycin or tumor necrosis factor α, can solve problems such as ignorance and affecting BMMSC function , achieve the effect of improving function, reducing bone loss and reducing bone density

Pending Publication Date: 2021-04-13
施松涛
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it is not known whether and how these MSC-derived cytokines affect BMMSC function

Method used

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  • Application of rapamycin or tumor necrosis factor alpha in preventing and/or treating diseases associated with mesenchymal stem cell injury
  • Application of rapamycin or tumor necrosis factor alpha in preventing and/or treating diseases associated with mesenchymal stem cell injury
  • Application of rapamycin or tumor necrosis factor alpha in preventing and/or treating diseases associated with mesenchymal stem cell injury

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089] The general experimental method that embodiment 1 present invention relates to

[0090] 1. Experimental materials

[0091] (1) ANIMAL. Female C57BL / 6J and B6.129S-Tnftm1Gk1 / J (TNFα- / -), B6.129S7-Ifngtm1Ts / J (IFNγ- / -), B6.129S2-Il6tm1Kopf / J (IL-6- / -), B6 .129S-TNFαsf1atm1ImxTNFαsf1btm1Imx / J(TNFα- / -), B6.Cg-Tg(Prrx1-cre)1Cjt / J(Prx1-Cre) and B6.Cg-Gt(ROSA)26Sortm9(CAG-tdTomato)Hze / J Mice were purchased from Jackson Lab and maintained at least 10 backcrosses in the C57BL / 6J background. Age-matched female littermates were used in all experiments. Female immunocompromised nude mice (Beige nu / nuXIDIII) were purchased from Harlan.

[0092] (2) Animal model, that is, hindlimb unloading. Mice were randomly divided into three groups: control group, unloading group and rapamycin-treated group. Mice in the unloaded group were subjected to continuous hindlimb suspension for 2 weeks. Hindlimb unloading was performed as previously described (Egawa et al., 2015). Briefly, the ta...

Embodiment 2

[0110] Example 2. TNFα is required to maintain BMMSC homeostasis through a TNF receptor-independent pathway.

[0111] 1. Experimental materials

[0112] (1) ANIMAL. Please refer to the experimental materials in Part 1 of Example 1.

[0113] 2. Experimental method

[0114] Please refer to the experimental method (1)-(15) of the second part of Example 1.

[0115] 3. Experimental results

[0116] To examine whether MSC-produced cytokines could modulate stem cell properties in BMMSCs, TNFα knockout (TNFα- / -), interferon-γ knockout (IFNγ- / -) and interleukin-6 knockout (IL- 6- / -) mice were used as a cytokine-deficient model to examine BMMSC function. found that TNFα- / -, but not IFNγ- / - and IL-6- / -, BMMSCs showed significantly reduced colony-forming unit fibroblast numbers (CFU-F; figure 1 A and Figure 8 A) and significantly reduced proliferation rate as assessed by toluidine blue staining and BrdU labeling assays, respectively ( figure 1 B and Figure 8 B). When cultured ...

Embodiment 3

[0122] Example 3. Endocytic TNFα inhibits mTOR activation by binding to mTOR complex 2.

[0123] 1. Experimental materials

[0124] (1) ANIMAL. Please refer to the experimental materials in Part 1 of Example 1.

[0125] 2. Experimental method

[0126] Please refer to the experimental method (1)-(15) of the second part of Example 1.

[0127] 3. Experimental results

[0128] Since TNFα protein was detected in TNFα- / - BMMSC lysates after mTNFα treatment, as analyzed by Western blot ( Figure 9 B and 3B) Assessed, it is hypothesized that mTNF[alpha] can be internalized by endocytosis. To test this hypothesis, TNFα- / - BMMSCs were treated with FITC-tagged mTNFα (FITC-TNFα), followed by immunofluorescence (IF) microscopy to detect FITC-TNFα in the cytoplasm; it mainly surrounds the nuclear region ( image 3 A). Furthermore, FITC-tagged TNFα was detected in TNFα- / - BMMSCs, suggesting that TNFα endocytosis is independent of TNF receptors ( image 3 A). Next, apply the CMst inh...

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Abstract

The invention relates to prevention and treatment of diseases associated with mesenchymal stem cell injury. The invention relates to application of rapamycin or a tumor necrosis factor alpha in preventing and / or treating diseases associated with mesenchymal stem cell injury.

Description

technical field [0001] The present invention relates to the field of prevention and / or treatment of diseases related to damage of mesenchymal stem cells. Specifically, the present invention relates to the use of rapamycin or tumor necrosis factor alpha (TNFα) for the prevention and / or treatment of diseases associated with mesenchymal stem cell damage. Background technique [0002] TNFα is a pro-inflammatory cytokine responsible for immune regulation through its receptor-mediated signaling. Originally discovered as a factor associated with killing tumor cells, TNFα is a proinflammatory cytokine responsible for immune regulation (Beutler et al., 1985; Carswell et al., 1975; Kelker et al., 1985; Malaviya et al., 1996; Pennica et al., 1984). Transmembrane TNFα, also known as precursor TNFα (pro-TNFα), is a 26 kDa protein expressed on the cell surface of monocytes / macrophages, NK cells, activated T cells and various non-immune cells such as endothelial cells. Pro-TNFα is cleave...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/436A61K38/19A61P19/10
CPCA61K31/436A61K38/191A61P19/10
Inventor 施松涛
Owner 施松涛
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