Post-stroke pain (PSP) has an incidence of approximately 28.6% and is mostly secondary to central or peripheral nerve injury after ischemic or hemorrhagic stroke. It is characterized by persistent burning pain, tingling, or paresthesia, often accompanied by emotional disorders and functional disability 1. At present, clinical treatments are mainly based on drug administration, physical therapy, and nerve block. Although these approaches can temporarily alleviate the pain symptoms, they lack repair methods targeting the nerve injury itself, leading to high rates of pain recurrence and limited therapeutic efficacy. With the rapid development of regenerative medicine technology, human induced pluripotent stem cell (hiPSC)-derived organoids have shown great potential for repair and treatment in various fields, including the liver, kidneys, and nervous system, through their advantages of accurately simulating the pathophysiological characteristics of human tissues, enabling personalized construction, and possessing multicell synergistic functions. In the field of neural repair, neural organoids are expected to reproduce the cellular composition and structural characteristics of neural tissue, simulate the pathological microenvironment after nerve injury, and provide new research directions and therapeutic carriers for neural repair in PSP patients 2. By combining the research progress in organoid technology and neuropathic pain in recent years, this letter systematically discusses the feasibility of organoid use for neural repair in PSP patients. By optimizing the induction protocols in recent years, researchers have become able to directionally induce hiPSCs and construct brain organoids and spinal cord organoids that contain various types of neural cells, such as neurons, astrocytes, microglia, and oligodendrocytes 3. Some organoids can form preliminary neural circuits and vascular networks with primary neural signal transmission functions. For example, a research team at Johns Hopkins University successfully constructed multi-region brain organoids that contained more than 80% of common neural cell types by adding induction factors, such as brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. These multi-region brain organoids were able to generate electrical activity and respond as a network, thereby simulating some physiological functions of the human fetal brain at 40 days of age 4. Vascularization is key to the survival and function of neural organoids after transplantation. At present, researchers can achieve vascularization of neural organoids using two methods 5. First, they can co-culture neural organoids with vascular endothelial cells and add pro-angiogenic factors, such as vascular endothelial growth factor, to induce the formation of functional vascular networks within the organoids. Second, they can modify organoids with biohydrogel scaffolds and load them with vascular endothelial progenitor cells to achieve rapid integration with the host vascular system after transplantation. As an example, integration of neural organoids with microfluidic systems was shown to assist in creating a dynamic and perfusable vascular network that effectively delivered oxygen and nutrients, removed metabolic waste products, and promoted the maturation and functional stability of transplanted organoids 6. Neural organoids also possess significant immunomodulatory and neuroregenerative regulatory functions, which are highly consistent with the pathological repair needs for neuropathic pain sequelae. Organoids can regulate the host immune microenvironment, inhibit the inflammatory response at the nerve injury site, and reduce the formation of glial scars by secreting cytokines such as interleukin-4 and brain-derived neurotrophic factor, which is important because glial scars are the key barriers that hinder nerve axon regeneration and lead to intractable neuropathic pain 7. At the same time, the neurotrophic factors secreted by organoids can enhance the survival and proliferation of damaged nerve cells, induce nerve axon regeneration, and promote axon regeneration and neural circuit reconstruction. The organoid-based repair strategy for PSP centers on the concept of “improving blood perfusion, replenishing damaged neurons, and reconstructing neural circuits,” which can be divided into two main directions. The first is the combined transplantation strategy for vascular organoids and brain organoids. Ischemic stroke is often accompanied by local vascular infarction, and an insufficient blood supply aggravates nerve injury. Song et al. 5 confirmed that vascular organoids can undergo colonization in stroke model animals, integrate with the host blood vessels, and reconstruct functional networks. When combined with brain organoid transplantation to supplement nerve cells and promote axon regeneration, the pain threshold and function of the transplanted mice were significantly enhanced, with stable repair effects. Recently, a research team at the University of Minnesota Twin Cities combined 3D-printed neural scaffolds with spinal cord organoids to construct a “mini-spinal cord” that contained region-specific spinal neural progenitor cells, which was then transplanted into model rats simulating post-stroke central nervous system injury. The implanted cells differentiated into functional neurons and established synaptic connections with host nerves, effects that can improve motor function and are expected to reduce pain sensitivity 8. The second is the personalized organoid repair strategy. Owing to individual differences in the location and degree of nerve injury among stroke patients, autologous somatic cells isolated from the patients can be used to induce hiPSCs and construct personalized brain organoids that accurately simulate the pathological state of the nerve injury and achieve targeted repair, while also avoiding immune rejection after transplantation 9. The rapid development of organoid technology has provided a new pathway for the neural repair of neuropathic pain sequelae, such as PSP. The core advantages of this technology lie in accurately simulating the nerve injury microenvironment, realizing personalized repair, and balancing inflammatory regulation and neuroregeneration, which effectively make up for the limitations of current clinical treatments that relieve pain symptomatically but cannot repair nerve injury from the root cause. It is believed that through the gradual breakthrough of technical bottlenecks, organoid technology will move toward clinical applications, enabling an amendment of the treatment strategy for PSP from “symptomatic pain relief” to “root cause repair.” This would completely change the treatment pattern for this type of intractable neuropathic pain and confer new treatment hope on affected patients. Miao Lin: conceptualization, investigation, writing – original draft, funding acquisition. Xiaodong Chu: validation, formal analysis, writing – review and editing. Rong Zeng: conceptualization, funding acquisition, project administration, writing – review and editing. The authors have nothing to report. The authors have nothing to report. The authors have nothing to report. The authors declare no conflicts of interest. The authors have nothing to report.
Lin et al. (Fri,) studied this question.