Myoscaffolds reveal laminin scarring is detrimental for stem cell function while sarcospan induces compensatory fibrosis,npj Regenerative Medicine

当前位置： X-MOL 学术 › npj Regen. Med. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Myoscaffolds reveal laminin scarring is detrimental for stem cell function while sarcospan induces compensatory fibrosis
npj Regenerative Medicine ( IF 6.4 ) Pub Date : 2023-03-15 , DOI: 10.1038/s41536-023-00287-2
Kristen M Stearns-Reider _{1,

2} , Michael R Hicks _{3,

4,

5} , Katherine G Hammond ₁ , Joseph C Reynolds ₁ , Alok Maity _{1,

6,

7} , Yerbol Z Kurmangaliyev _{7,

8} , Jesse Chin ₁ , Adam Z Stieg ₉ , Nicholas A Geisse ₁₀ , Sophia Hohlbauch ₁₁ , Stefan Kaemmer ₁₂ , Lauren R Schmitt ₁₃ , Thanh T Pham ₁₃ , Ken Yamauchi _{4,

14} , Bennett G Novitch _{4,

14,

15,

16} , Roy Wollman _{1,

6,

7} , Kirk C Hansen ₁₃ , April D Pyle _{3,

4,

15} , Rachelle H Crosbie _{1,

4,

15,

17}

Affiliation

Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Department of Orthopaedic Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, 92697, USA.
Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Institute for Quantitative and Computational Biology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Department of Biological Chemistry, HHMI, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Curi Bio, Seattle, WA, 98121, USA.
Asylum Research, An Oxford Instruments Company, Santa Barbara, CA, 93117, USA.
Park Systems, 3040 Olcott St, Santa Clara, CA, 95054, USA.
Department of Biochemistry and Molecular Genetics, University of Colorado, Denver, Aurora, CO, 80045, USA.
Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.

We developed an on-slide decellularization approach to generate acellular extracellular matrix (ECM) myoscaffolds that can be repopulated with various cell types to interrogate cell-ECM interactions. Using this platform, we investigated whether fibrotic ECM scarring affected human skeletal muscle progenitor cell (SMPC) functions that are essential for myoregeneration. SMPCs exhibited robust adhesion, motility, and differentiation on healthy muscle-derived myoscaffolds. All SPMC interactions with fibrotic myoscaffolds from dystrophic muscle were severely blunted including reduced motility rate and migration. Furthermore, SMPCs were unable to remodel laminin dense fibrotic scars within diseased myoscaffolds. Proteomics and structural analysis revealed that excessive collagen deposition alone is not pathological, and can be compensatory, as revealed by overexpression of sarcospan and its associated ECM receptors in dystrophic muscle. Our in vivo data also supported that ECM remodeling is important for SMPC engraftment and that fibrotic scars may represent one barrier to efficient cell therapy.

中文翻译：

肌支架显示层粘连蛋白疤痕对干细胞功能有害，而肌跨会诱导代偿性纤维化

我们开发了一种滑动脱细胞方法来生成脱细胞细胞外基质 (ECM) 肌支架，该肌支架可以用各种细胞类型重新填充，以研究细胞与 ECM 的相互作用。利用这个平台，我们研究了纤维化 ECM 疤痕是否影响了对于肌肉再生至关重要的人类骨骼肌祖细胞 (SMPC) 功能。 SMPC 在健康肌肉来源的肌支架上表现出强大的粘附性、运动性和分化能力。所有 SPMC 与营养不良肌肉纤维化肌支架的相互作用都严重减弱，包括运动速率和迁移降低。此外，SMPC 无法重塑患病肌支架内的层粘连蛋白致密纤维化疤痕。蛋白质组学和结构分析表明，过度的胶原蛋白沉积本身并不是病理性的，并且可以是代偿性的，正如营养不良性肌肉中肌跨及其相关 ECM 受体的过度表达所揭示的那样。我们的体内数据还支持 ECM 重塑对于 SMPC 植入很重要，并且纤维化疤痕可能是有效细胞治疗的障碍之一。

更新日期：2023-03-16

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文