Does cellular niche affect the repair potential of mesenchymal stem cells; implications for spinal cord injury?

细胞生态位是否影响间充质干细胞的修复潜力？

• 批准号: MR/J004731/1
• 负责人: Susan Barnett
• 金额: $ 69.07万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ004731%2F1
• 关键词: Does; cellular; niche; affect; repair

Spinal cord injury (SCI) is a devastating injury where disruption of nerves leads to loss of communication between the brain and the spinal cord below the lesion resulting in paralysis and loss of sensation. The loss of function is often permanent because nerves are not able to grow again and restore the lost communication. Not all spinal cord injuries lead to a complete disruption of all of the nerve fibres. In about half the cases of spinal cord injury a variable number of nerve fibres remain and support some residual function. However, this remaining function is more limited than it ought to be because often the cells which provide the insulation (myelin sheath) around the nerves have been lost or damaged. This insulation normally enables the electrical impulses by which nerves signal to pass efficiently along their length and without it the nerves do not signal as effectively as they could. One strategy to repair the injured spinal cord is to transplant cells that can help effect some form of repair, including repair of the damaged insulation around the nerves. The nervous tissue associated with the sense of smell, known as the olfactory mucosa, has unusual regenerative properties not found in other nervous tissue, and this has lead to the idea that cells from this tissue may be particularly useful for the transplant-mediated repair of SCI. The properties of this tissue include continual synthesis throughout life of new nerves which originate from stem cells in the tissue, as well as the presence of special glial cells (olfactory ensheathing cells, OECs) which guide regenerating nerve processes back into the central nervous system (CNS) to reform connections. Cells from the olfactory mucosa have been shown to promote repair when transplanted into rat models of SCI and because of the reparative properties of these cells, clinical trials have been set up around the world, in which human olfactory mucosa or mixtures of olfactory cells have been transplanted into patients. However, the olfactory mucosa contains many different cell types and it is not clear which cells are beneficial for CNS repair. Recently, we have shown that the olfactory mucosa contains a novel stem cell (cells that are capable of becoming other cell types) in addition to the well-known OECs (cells that support regeneration of nerves). We have carried out detailed studies in dishes on the biological properties of these cells after taking them from the olfactory mucosa of laboratory rats or obtaining them from human donors undergoing surgery involving the nose. As a result of these studies, we have found that the stem cells obtained from both animals and humans secrete factors that help OECs to increase in number and to change their shape. We have also seen that they are able to encourage other cells present in the spinal cord, which normally form the insulation around nerves (oligodendrocyte precursor cells), to wrap a new layer of insulation (that is to form a myelin sheath) around nerves that have lost this due to damage. This could be a very useful property for the repair of SCI. For this reason we wish to obtain a better understanding of how these stem cells facilitate this process of re-insulation (remyelination) and to investigate how effectively they can do this in animal models of spinal cord injury. We hope the information that will be obtained will contribute importantly to the development of therapies that can improve the recovery of function after a spinal cord injury.

脊髓损伤（SCI）是一种毁灭性的损伤，神经破坏导致大脑和病变下方脊髓之间的沟通丧失，从而导致瘫痪和感觉丧失。功能的丧失通常是永久性的，因为神经不能再生长并恢复失去的交流。并不是所有的脊髓损伤都会导致所有神经纤维的完全断裂。在大约一半的脊髓损伤病例中，保留了数量不定的神经纤维，并支持一些残余功能。然而，这种剩余的功能比它应有的功能更有限，因为在神经周围提供绝缘的细胞（髓鞘）经常已经丢失或损坏。这种绝缘通常能使电脉冲使神经信号沿其长度有效地传递，没有它，神经信号就不能有效地传递。修复受损脊髓的一种策略是移植细胞，这种细胞可以帮助实现某种形式的修复，包括修复神经周围受损的绝缘。与嗅觉相关的神经组织，被称为嗅觉粘膜，具有其他神经组织所没有的不寻常的再生特性，这导致了来自该组织的细胞可能对移植介导的脊髓损伤修复特别有用的想法。这种组织的特性包括在整个生命周期中不断合成来自组织中干细胞的新神经，以及特殊胶质细胞（嗅鞘细胞，OECs）的存在，这些胶质细胞引导再生的神经过程回到中枢神经系统（CNS）以重建连接。来自嗅觉粘膜的细胞在移植到大鼠脊髓损伤模型中显示出促进修复的作用，由于这些细胞的修复特性，世界各地已经建立了临床试验，将人类嗅觉粘膜或嗅觉细胞混合物移植到患者身上。然而，嗅觉粘膜包含许多不同类型的细胞，目前尚不清楚哪些细胞对中枢神经系统的修复有益。最近，我们已经证明，嗅觉粘膜除了已知的oec（支持神经再生的细胞）外，还含有一种新的干细胞（能够成为其他细胞类型的细胞）。我们已经在培养皿中对这些细胞的生物学特性进行了详细的研究，这些细胞是从实验室大鼠的嗅觉粘膜中提取的，或者是从接受鼻子手术的人类供体中获得的。通过这些研究，我们发现从动物和人类身上获得的干细胞都能分泌有助于oec数量增加和形状改变的因子。我们还看到，它们能够促使脊髓中存在的其他细胞（通常形成神经周围的绝缘层）（少突胶质前体细胞）在因损伤而失去绝缘层的神经周围包裹一层新的绝缘层（即形成髓鞘）。这对脊髓损伤的修复是非常有用的。因此，我们希望更好地了解这些干细胞如何促进这种再绝缘（髓鞘再生）过程，并研究它们在脊髓损伤动物模型中如何有效地做到这一点。我们希望将获得的信息将有助于治疗的发展，可以提高脊髓损伤后的功能恢复。

项目成果

The multifaceted role of astrocytes in regulating myelination.

• DOI: 10.1016/j.expneurol.2016.03.009
• 发表时间: 2016-09
• 期刊: EXPERIMENTAL NEUROLOGY
• 影响因子: 5.3
• 作者: Kiray, Hulya;Lindsay, Susan L.;Hosseinzadeh, Sara;Barnett, Susan C.
• 通讯作者: Barnett, Susan C.

Are nestin-positive mesenchymal stromal cells a better source of cells for CNS repair?

• DOI: 10.1016/j.neuint.2016.08.001
• 发表时间: 2017-06
• 期刊: Neurochemistry international
• 影响因子: 4.2
• 作者: Lindsay SL;Barnett SC
• 通讯作者: Barnett SC

Human olfactory mesenchymal stromal cell transplantation ameliorates experimental autoimmune encephalomyelitis revealing an inhibitory role for IL16 on myelination.

人类嗅觉间充质基质细胞移植可以改善实验性自身免疫性脑脊髓炎，揭示了IL16在髓鞘中的抑制作用。

• DOI: 10.1186/s40478-022-01316-9
• 发表时间: 2022-01-29
• 期刊: Acta neuropathologica communications
• 影响因子: 7.1
• 作者: Lindsay SL;Molęda AM;MacLellan LM;Keh SM;McElroy DE;Linington C;Goodyear CS;Barnett SC
• 通讯作者: Barnett SC

Human olfactory mesenchymal stromal cell transplants promote remyelination and earlier improvement in gait co-ordination after spinal cord injury.

• DOI: 10.1002/glia.23117
• 发表时间: 2017-04
• 期刊: Glia
• 影响因子: 6.2
• 作者: Lindsay SL;Toft A;Griffin J;M M Emraja A;Barnett SC;Riddell JS
• 通讯作者: Riddell JS

Therapeutic Potential of Niche-Specific Mesenchymal Stromal Cells for Spinal Cord Injury Repair.

• DOI: 10.3390/cells10040901
• 发表时间: 2021-04-14
• 期刊: Cells
• 影响因子: 6
• 作者: Lindsay SL;Barnett SC
• 通讯作者: Barnett SC