The immune microenvironment and tissue engineering strategies for spinal cord regeneration

Abstract

Regeneration of neural tissue is limited following spinal cord injury (SCI). Successful regeneration of injured nerves requires the intrinsic regenerative capability of the neurons and a suitable microenvironment. However, the local microenvironment is damaged, including insufficient intraneural vascularization, prolonged immune responses, overactive immune responses, dysregulated bioenergetic metabolism and terminated bioelectrical conduction. Among them, the immune microenvironment formed by immune cells and cytokines plays a dual role in inflammation and regeneration. Few studies have focused on the role of the immune microenvironment in spinal cord regeneration. Here, we summarize those findings involving various immune cells (neutrophils, monocytes, microglia and T lymphocytes) after SCI. The pathological changes that occur in the local microenvironment and the function of immune cells are described. We also summarize and discuss the current strategies for treating SCI with tissue-engineered biomaterials from the perspective of the immune microenvironment.

Comprehensive landscape of immune-based classifier related to early diagnosis and macrophage M1 in spinal cord injury

“…Despite the multiple methods that have been utilized to manage spinal cord injuries, including surgical decompression, pharmacotherapy, and physical rehabilitation, most patients still do not receive sufficient outcomes [4]. Consistent with the classic response to most organ injuries, SCI can trigger an intense immune inflammatory response, causing a rapid increase in circulating neutrophils, accompanied by immediate recruitment and infiltration of immune cells such as monocytes into the injured spinal cord site [15]. The immune response is a normal physiological consequence of the dramatic changes in the microenvironment following SCI, but this excessive response can entail further damage to spinal cord tissues, prevent repair and regeneration of spinal cord neurons, and ultimately worsen the clinical outcomes [6].…”

“…Following SCI, myeloid neutrophils rapidly enter the bloodstream and migrate and accumulate in the injured spinal cord through the endothelial barrier, exacerbating tissue inflammatory damage [23]. Activated neutrophils not only engulf localized necrotic tissue but also release elastase and reactive oxygen species to damage neurons and aggravate neurological dysfunction [15]. The infiltrating macrophages in the injured spinal cord consist of two sources, resident microglia and the peripheral source of myeloid macrophages.…”

“…A variety of immune cells are involved in the inflammatory response after SCI, including neutrophils, macrophages, B lymphocytes, and T lymphocytes, which can remain at the site of injury long and exert different functions in response to the injury phases and altered signaling in the microenvironment [13,14]. An increasing number of studies have demonstrated that the inflammatory microenvironment formed from immune cells and cytokines has a dual role in the regenerative and repair processes in SCI [15]. For instance, macrophages are capable of forming both a proinflammatory response in the injured spinal cord to exacerbate tissue damage and an anti-inflammatory signal to protect neuronal cells [16].…”

Combination of single-cell and bulk RNA seq reveals the immune infiltration landscape and targeted therapeutic drugs in spinal cord injury

“…SCI often leads to irreversible neurological impairment and also has a significant socioeconomic impact on both the patients and the healthcare system ( 16 ). The altered immune microenvironment after SCI hinders neural regeneration and repair, but related studies have been met with conflicting findings ( 17 ). Next-generation sequencing is a novel modality that enabled the discovery of the altered immune microenvironment after SCI ( 18 ).…”

Neuronal regeneration after injury: a new perspective on gene therapy

“…NG2 glial cells in the spinal cord also have neurogenic potential and can be reprogrammed through ectopic SOX2 expression, promoting functional neurogenesis and injury recovery (Wang and Zhang, 2018;Tai et al, 2021). Pericytes, which are cells that wrap around capillaries and regulate blood flow (Bergers and Song, 2005), and microglia, which are immune cells in the spinal cord, have also shown the potential to be reprogrammed into functional neurons in culture (Matsuda et al, 2019;Cakir et al, 2022;Feng et al, 2022). However, achieving sufficient neuronal reprogramming for repair without overly disrupting the physiological function of these cells is a crucial consideration.…”