Department of Neurosurgery, First Hospital of Jilin University, Changchun, 130021, China.
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China; Key Laboratory of Molecular Epigenetics, Institute of Genetics and Cytology, Northeast Normal University, 130024, China.
Acta Biomater. 2022 Sep 15;150:67-82. doi: 10.1016/j.actbio.2022.07.018. Epub 2022 Jul 13.
Stem cell treatment is vital for recovery from traumatic brain injury (TBI). However, severe TBI usually leads to excessive inflammation and neuroinhibitory factors in the injured brain, resulting in poor neural cell survival and uncontrolled formation of glial scars. In this study, a bioorthogonal microenvironment was constructed on biodegradable poly(lactide-co-glycolide) (PLGA) microcarriers through immobilization of mussel-inspired bioorthogonal 3,4-dihydroxyphenylalanine-containing recombinant nerve growth factor (DOPA-NGF) and human umbilical cord mesenchymal stem cells (hUMSCs) for minimally invasive therapy of TBI. Cell culture and RNA-seq analysis revealed enhanced extracellular matrix (ECM) secretion and viability of hUMSCs on PLGA microcarriers compared to 2D culture. Immobilized DOPA-NGF further promoted adhesion, proliferation, and gene expression in RSC96 neurotrophic cells and hUMSCs. Specifically, the neurotrophin receptor of NT-3 (NTRK3) in hUMSCs was activated by DOPA-NGF, leading to MYC transcription and paracrine enhancement to build an adjustable biomimetic microenvironment. After transplantation of microunits in animal models, the motor and learning-memory ability of TBI mice were improved through rollbacks of overactivated inflammatory reaction regulation, neuronal death, and glial scar formation after injury. This was attributed to the paracrine enhancement of hUMSCs activated by the DOPA-NGF. Our study provides a neural regenerative microenvironment-based therapeutic strategy to advance the effects of transplanted hUMSCs in cell-based regenerative medicine for TBI therapy. STATEMENT OF SIGNIFICANCE: Extensive studies have demonstrated the importance of the microenvironment for posttraumatic brain injury recovery. However, an efficient method that can mimic the neural regenerative microenvironment to strengthen stem cell therapy and brain injury recovery is still absent. In this study, the minimally invasive transplantation of DOPA-NGF immobilized biodegradable microcarriers with mesenchymal stem cells was found to be an effective method for regeneration of injured brain. Moreover, transcriptome analysis revealed that neurotrophin receptor of NT-3 (NTRK3) was activated by DOPA-NGF for MYC transcription and paracrine enhancement to build a kind of adjustable biomimetic microenvironment for brain injury therapy. This study provides a neural regenerative microenvironment-based therapeutic strategy to advance the transplanted hUMSCs in cell-based regenerative medicine for neural recovery.
干细胞治疗对于创伤性脑损伤（TBI）的恢复至关重要。然而，严重的 TBI 通常会导致受伤大脑中过度的炎症和神经抑制因子，导致神经细胞存活不良和神经胶质瘢痕的不受控制形成。在这项研究中，通过固定贻贝启发的生物正交 3,4-二羟基苯丙氨酸含有的重组神经生长因子（DOPA-NGF）和人脐带间充质干细胞（hUMSC），在可生物降解的聚（乳酸-共-乙醇酸）（PLGA）微载体上构建了生物正交微环境，用于 TBI 的微创治疗。细胞培养和 RNA-seq 分析表明，与 2D 培养相比，hUMSC 在 PLGA 微载体上的细胞外基质（ECM）分泌和活力增强。固定的 DOPA-NGF 进一步促进了 RSC96 神经营养细胞和 hUMSC 的粘附、增殖和基因表达。具体而言，DOPA-NGF 激活了 hUMSC 中的神经营养因子受体 NT-3（NTRK3），导致 MYC 转录和旁分泌增强，以构建可调节的仿生微环境。在动物模型中移植微单位后，通过逆转损伤后过度激活的炎症反应调节、神经元死亡和神经胶质瘢痕形成，改善了 TBI 小鼠的运动和学习记忆能力。这归因于 DOPA-NGF 激活的 hUMSC 的旁分泌增强。我们的研究提供了一种基于神经再生微环境的治疗策略，以推进基于细胞的再生医学中移植的 hUMSC 在 TBI 治疗中的作用。
大量研究表明微环境对创伤后脑恢复的重要性。然而，仍然缺乏一种能够模拟神经再生微环境以增强干细胞治疗和脑损伤恢复的有效方法。在这项研究中，发现用生物可降解微载体固定 DOPA-NGF 和间充质干细胞的微创移植是一种有效的方法，可用于受伤大脑的再生。此外，转录组分析表明，神经营养因子受体 NT-3（NTRK3）被 DOPA-NGF 激活，用于 MYC 转录和旁分泌增强，以建立一种可调节的仿生微环境，用于脑损伤治疗。这项研究提供了一种基于神经再生微环境的治疗策略，以推进基于细胞的再生医学中移植的 hUMSC 在神经恢复中的作用。
