Stem cell exosomes: New hope for recovery from diabetic brain hemorrhage

Table 1 Key mechanisms of action of stem cell–derived exosomes for neurological recovery post–diabetic cerebral hemorrhage

Mechanism of action	Description	Ref.
miR-129-5p modulation	Bone marrow–derived mesenchymal stem cell–derived exosomes deliver miR-129-5p, which targets and downregulates HMGB1. This leads to reduced neuroinflammation and improved neurological outcomes	Wang et al[1], 2024
Attenuation of oxidative stress	Exosomes reduce oxidative stress by modulating the expression of antioxidant enzymes and by reducing the production of reactive oxygen species, thereby protecting neurons from damage	Gómez-de Frutos et al[2], 2024
Promotion of neurogenesis	Stem cell–derived exosomes promote neurogenesis by delivering growth factors and microRNAs that support the proliferation and differentiation of neural progenitor cells in the damaged brain	Cheng et al[4], 2024
Inhibition of apoptosis	Exosomes carry antiapoptotic signals, such as miRNAs and proteins, which inhibit the activation of apoptotic pathways in neurons, reducing cell death in the affected brain regions	Larsson et al[3], 2024
Reduction of blood–brain barrier disruption	Bone marrow–derived mesenchymal stem cell–derived exosomes strengthen the blood–brain barrier by enhancing tight junction protein expression and reducing vascular permeability, thus preventing further brain injury post-hemorrhage	Lv et al[5], 2024
Modulation of immune response	Exosomes modulate the immune response by altering the activity of microglia and macrophages, reducing the production of proinflammatory cytokines, and promoting a neuroprotective environment	Southerland et al[6], 2024
Enhancement of angiogenesis	Bone marrow–derived mesenchymal stem cell–derived exosomes promote angiogenesis by delivering proangiogenic factors such as VEGF, which support the formation of new blood vessels and improve blood supply to the injured brain tissue	Wang et al[1], 2024
Regulation of autophagy	Exosomes influence autophagy processes in neurons and glial cells, contributing to the clearance of damaged proteins and organelles and supporting cellular homeostasis and survival	Wang et al[1], 2024
miRNA-mediated gene expression modulation	Through the delivery of various miRNAs, exosomes modulate the expression of genes involved in inflammation, cell survival, and repair processes, facilitating recovery from brain injury	Gómez-de Frutos et al[2], 2024
Neuroprotection through anti-inflammatory effects	Bone marrow–derived mesenchymal stem cell–derived exosomes reduce the expression of proinflammatory genes and increase anti-inflammatory cytokines, protecting neural tissue from secondary damage post-hemorrhage	Cheng et al[4], 2024

The table presents the key mechanisms through which stem cell–derived exosomes contribute to neurological recovery following diabetic cerebral hemorrhage. These exosomes modulate various molecular pathways, including the regulation of miR-129-5p, oxidative stress reduction, neurogenesis promotion, apoptosis inhibition, and immune response modulation. They also play a crucial role in strengthening the blood–brain barrier, enhancing angiogenesis, and regulating autophagy, thereby offering a multifaceted therapeutic approach to mitigating brain injury and promoting recovery. HMGB1: High-mobility group box 1; VEGF: Vascular endothelial growth factor.

Table 2 Comparative analysis of miR-129-5p modulation and high-mobility group box 1 targeting in diabetic and nondiabetic cerebral hemorrhage

Mechanism	Diabetic cerebral hemorrhage	Nondiabetic cerebral hemorrhage	Ref.
miR-129-5p modulation	Regulates neuroinflammation: MiR-129-5p from bone marrow–derived mesenchymal stem cell–derived exosomes modulates neuroinflammation by targeting HMGB1, which reduces neurological impairment and oxidative stress	Modulates neuroinflammation and cellular stress: Similar pathways involving miR-129-5p can modulate inflammation and oxidative stress, but they are less studied in nondiabetic contexts	Wang et al[1], 2024; Gómez-de Frutos et al[2], 2024
HMGB1 targeting	Attenuates damage: Targeting HMGB1 with miR-129-5p-loaded exosomes can alleviate brain damage by reducing inflammatory responses and promoting cellular repair	Reduces inflammation and promotes recovery: Targeting HMGB1 may reduce inflammation and support recovery, but the specific mechanisms and efficacy may differ because of the absence of diabetes-related complications	Wang et al[1], 2024; Cheng et al[4], 2024
Impact on neurological outcomes	Improves outcomes significantly: Enhanced targeting of HMGB1 and reduction in neuroinflammation lead to more favorable recovery in diabetic cerebral hemorrhage models	Varied outcomes: The efficacy of HMGB1 targeting in nondiabetic hemorrhages can be variable, with outcomes influenced by the absence of diabetes-related factors	Gómez-de Frutos et al[2], 2024; Larsson et al[3], 2024
Mechanistic differences	Diabetes-specific effects: The presence of diabetes affects the baseline inflammatory state and cellular response, influencing how miR-129-5p and HMGB1 targeting modify outcomes	General mechanisms: In nondiabetic conditions, the effects of miR-129-5p and HMGB1 targeting are based on standard inflammatory pathways without additional diabetes-related complications	Lv Y et al[5], 2024; Southerland et al[6], 2024

This table provides a comparative analysis of the modulation of miR-129-5p and targeting of high-mobility group box 1 in diabetic vs nondiabetic cerebral hemorrhage. The differential impact on neuroinflammation, neurological outcomes, and specific mechanisms are highlighted to illustrate the variations in therapeutic efficacy and response between diabetic and nondiabetic conditions. HMGB1: High-mobility group box 1.

Table 3 Potential clinical applications and future directions for exosome-based therapies for diabetic neurological complications

Application/direction	Clinical application	Future directions	Ref.
Exosome-based delivery of miR-129-5p	Targeted therapy: Exosomes derived from bone marrow mesenchymal stem cells loaded with miR-129-5p can target HMGB1, potentially attenuating neurological impairments in diabetic cerebral hemorrhage	Expand research: Investigate the effectiveness of miR-129-5p-loaded exosomes in broader diabetic and nondiabetic neurological conditions and optimize exosome delivery systems for enhanced therapeutic efficacy	Wang et al[1], 2024
Reduction of inflammation through exosomal cargo	Anti-inflammatory effects: Exosomes can deliver anti-inflammatory agents to mitigate neuroinflammation in diabetic cerebral hemorrhage	Explore mechanisms: Study the specific exosomal components responsible for reducing inflammation and their impacts on long-term outcomes in diabetic patients	Gómez-de Frutos et al[2], 2024
Exosome-mediated neuroprotection	Neuroprotective strategies: Utilizing exosomes to deliver neuroprotective agents can reduce oxidative stress and cell death in diabetic neurological complications	Develop neuroprotective formulations: Focus on formulating exosomes with neuroprotective agents and assessing their safety and efficacy in clinical trials	Cheng et al[4], 2024
Biomarker discovery and monitoring	Diagnostic tool: Exosomal microRNAs can serve as biomarkers for the early diagnosis and monitoring of disease progression in diabetic neurological disorders	Validate biomarkers: Conduct longitudinal studies to validate exosomal biomarkers and their predictive value for disease outcomes	Liao et al[8], 2023
Combination therapies	Synergistic approaches: Combining exosome-based therapies with other treatments, such as hyperglycemia management and lifestyle modifications, can enhance overall therapeutic efficacy	Integrate therapies: Explore synergistic effects of combining exosome-based therapies with traditional and novel treatments in clinical settings	Su et al[7], 2024
Personalized medicine	Tailored treatments: Personalized exosome-based therapies can be developed on the basis of individual patient profiles and specific disease mechanisms	Customize approaches: Research personalized exosome-based treatments tailored to the genetic and metabolic profiles of diabetic patients	Zeinhom et al[9], 2024

This table outlines the potential clinical applications and future research directions for exosome-based therapies for managing diabetic neurological complications. It highlights the current therapeutic uses, anticipated advancements, and areas requiring further investigation to optimize these novel treatments. HMGB1: High-mobility group box 1.