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. 2025 Jul 11;26(4):143. doi: 10.1007/s10522-025-10282-3

Advances in brain remodeling, stem cell therapies, and translational barriers in stroke and brain aging

Bogdan Capitanescu 3,#, Dirk M Hermann 1,3,#, Roxana Surugiu 3, Raphael Guzman 2, Denissa Greta Olaru 3,✉, Aurel Popa-Wagner 1,3,✉
PMCID: PMC12254094  PMID: 40643679

Abstract

As the brain ages, it undergoes a series of molecular and cellular changes that affect its structure and function, contributing to age-related disorders—particularly cerebrovascular diseases and diminished regenerative capacity following ischemic injury. Despite significant research efforts, effective therapies for brain rewiring and functional recovery after cerebral ischemia remain elusive. A deeper understanding of the cellular and molecular mechanisms involved in the post-acute phase of stroke may help identify novel therapeutic strategies for age-associated vascular pathologies. Recent advances have highlighted several promising areas, including epigenetic modifications of the vascular wall, blood–brain barrier remodeling, cell- and subcellular-based therapies, and innovative delivery methods. However, despite encouraging preclinical findings, clinical trials have produced mixed results regarding the safety and efficacy of cell-based interventions. These outcomes suggest that successful stroke therapies in aging populations may require a multistage, integrative approach.

Keywords: Brain aging, Cerebrovascular diseases, Regenerative capacity, Brain plasticity, Cell therapies, Routes of administration

Introduction

As the brain ages, it undergoes a series of molecular and cellular changes that gradually alter its structure and function. Numerous recent reviews have explored the genetic, molecular, metabolic, and cellular pathways that collectively drive the complex and inevitable process of brain aging (Tacutu et al. 2011). Anatomically, aging is associated with reductions in gray matter volume—particularly in the frontal and parietal lobes—leading to cortical thinning and widened sulci. These structural alterations are linked to cognitive declines, notably in memory, attention, and language processing.

At the physiological level, brain aging is marked by a progressive loss of homeostatic regulation. Single-cell transcriptomic analyses in aging mouse brains have identified the third ventricle of the hypothalamus—an essential center for systemic homeostasis—as particularly vulnerable to aging. Within this region, nuclei such as the arcuate, dorsomedial, and paraventricular express genes critical for energy balance and homeostatic control.

Functional changes are further reflected in the decline of neurovascular integrity, neurotransmitter signaling, and synaptic plasticity, all of which collectively impair the brain’s adaptive capacity. Aging neurons exhibit diminished mitochondrial efficiency and increased oxidative stress, while glial cells such as astrocytes and microglia display a shift toward pro-inflammatory phenotypes, a process known as “inflammaging” (Hou et al. 2019; Liddelow et al. 2020). These glial changes contribute to a chronically altered neuroimmune environment that exacerbates neuronal vulnerability and impairs repair mechanisms. Moreover, the reduced efficacy of neurogenesis in the hippocampus and the subventricular zone limits the brain’s ability to replace lost or damaged cells, further compromising cognitive resilience (Daynac et al. 2016; Smith et al. 2018; Toda et al. 2019; Kim et al. 2022).

In this context, the present review focuses on the age-related decline in brain plasticity, a key factor that compromises the brain’s capacity to recover from major injuries, including cerebral ischemia. Understanding the mechanisms underlying the loss of plasticity is essential for identifying therapeutic strategies aimed at enhancing regenerative capacity and improving functional outcomes in the aging brain. Special emphasis is placed on the interplay between neuroinflammation, metabolic dysfunction, and impaired cellular regeneration as central contributors to this decline (Jin et al. 2004; Popa-Wagner et al. 2020).

Cell death mechanisms in cerebral ischemia–reperfusion injury

Cerebral ischemia, characterized by a reduction in blood flow to the brain, leads to neuronal injury and activates complex molecular mechanisms aimed at tissue repair and remodeling. In the aging brain, these processes are often less efficient, resulting in impaired recovery and increased susceptibility to further damage. Understanding these processes is crucial for developing therapeutic strategies to mitigate age-related post-acute recovery after cerebral ischemia (Popa-Wagner et al. 2007).

Cerebral ischemia–reperfusion injury involves various cell death mechanisms, including apoptosis, necrosis, necroptosis, autophagy, pyroptosis, and ferroptosis. These pathways are interconnected and contribute to neuronal damage. A comprehensive understanding of these mechanisms is crucial for developing targeted therapies to mitigate brain injury following ischemic events (Zhang et al. 2022).

Cerebrovascular morphology in aging and disease

Altered brain vasculature is a hallmark of numerous neurological disorders and has garnered growing attention as both a contributor to pathophysiology and a potential diagnostic target. Quantitative assessments of vascular morphology—employing advanced imaging techniques such as MRI, CT angiography, and 3D vessel segmentation—have provided insight into structural and functional changes in the cerebrovascular system of healthy individuals and those affected by neurological disease. These studies encompass evaluations across the adult lifespan, revealing age-related reductions in vessel density, increased tortuosity, and diminished cerebrovascular reactivity, as well as considerable anatomical variation in critical regions like the Circle of Willis. Such variability may influence individual susceptibility to ischemic events and impact the effectiveness of collateral circulation during cerebrovascular incidents (Mandalà and Cipolla 2021).

In acute ischemic stroke, patients exhibit marked alterations in vascular geometry, including vessel narrowing, irregular branching, and disrupted perfusion territories, which correlate with infarct volume and clinical outcome. These abnormalities often reflect a combination of atherosclerotic burden, endothelial dysfunction, and inflammatory processes that impair vascular integrity. Similarly, in Alzheimer’s disease (AD), cerebrovascular remodeling is a prominent feature even in early or prodromal stages. Pathological changes such as amyloid-beta accumulation within vessel walls (cerebral amyloid angiopathy), basement membrane thickening, and endothelial cell degeneration contribute to chronic hypoperfusion, impaired blood–brain barrier function, and subsequent neuronal injury. Notably, these vascular changes can precede overt cognitive symptoms, supporting the hypothesis that vascular pathology is not merely a consequence but also a potential driver of neurodegeneration (Farkas and Luiten 2001; Rather et al. 2024).

Emerging evidence supports the utility of cerebral vascular morphology as a non-invasive imaging biomarker for neurological diseases, potentially aiding in early diagnosis, risk stratification, and therapeutic monitoring. Recent studies utilizing ultra-high-field MRI and AI-based vascular segmentation algorithms have enhanced the sensitivity and specificity of detecting microvascular abnormalities in conditions like stroke and AD. Furthermore, longitudinal vascular imaging in aging cohorts has provided predictive insights into cognitive decline and dementia conversion (Deshpande et al. 2022; Hao et al 2024). These findings underscore the relevance of vascular geometry not only in understanding disease mechanisms but also in guiding clinical decision-making.

Epigenetic modifications in vascular pathological aging

Aging is associated with alterations in DNA methylation and histone modifications, leading to changes in gene expression. DNA methylation biomarkers can estimate the biological age of any tissue across the entire human lifespan, including during development. These epigenetic clocks are now widely used to investigate epigenetic age acceleration, cancer, and age-related disorders, such as metabolic diseases and cognitive decline in the elderly (Wang et al. 2022a, b; Salameh et al. 2020).

Epigenetic modifications, including DNA methylation, histone modifications, and non-coding RNA regulation, play pivotal roles in vascular aging and related pathologies (Fraile-Martinez et al. 2024). These alterations can influence gene expression without changing the underlying DNA sequence, thereby affecting vascular function and contributing to age-related diseases. DNA methylation, the addition of methyl groups to DNA molecules, has been implicated in various cardiovascular conditions (Ermakova et al. 2024). In atherosclerosis, for instance, studies have shown that vascular tissues exhibit global hypomethylation alongside gene-specific hypermethylation, which may serve as early biomarkers for the disease. Elevated homocysteine levels, a known cardiovascular risk factor, can inhibit DNA methyltransferases, leading to hypomethylation and subsequent gene expression changes that promote atherosclerotic lesion formation (Zhu et al. 2021; Ma et al. 2024a, b).

Histone modifications, such as methylation and acetylation, also significantly impact vascular aging. The histone mark H3K9me2, for example, is present at certain cardiovascular disease-associated gene promoters in vascular smooth muscle cells, where it can block the binding of transcription factors like NFκB and AP-1. Reduced levels of H3K9me2 have been observed in vascular smooth muscle cells from human atherosclerotic lesions compared to healthy tissue, suggesting its role in vascular pathology (Harman et al. 2019; Lambert and Jørgensen 2025).

Epigenetic alterations can impact gene expression and influence stroke outcomes (Gallizioli et al. 2023). For instance, DNA methylation profiling of post-stroke brain microvessels revealed differentially methylated regions associated with genes involved in cell junctions, actin remodeling, and signaling pathways, which may affect blood–brain barrier recovery (Phillips et al. 2023). Additionally, histone modifications and non-coding RNAs have been implicated in secondary brain injuries post-stroke, suggesting their potential as therapeutic targets. Therefore, understanding these epigenetic mechanisms is crucial for developing strategies to enhance recovery and mitigate the effects of stroke in the aging brain (Peng et al. 2022).

Molecular mechanisms of brain remodeling in the aged brain and in the aged brain post-ischemia

In response to ischemic injury, the brain initiates neurovascular remodeling, involving the proliferation and migration of neural precursor cells, angiogenesis, and glial activation. However, in aged individuals, these processes are compromised. Studies have shown that restorative brain responses differ between young and old animals and are also modulated by age-related vascular risk factors such as atherosclerosis, diabetes, and hyperlipidemia. This suggests that age and associated comorbidities should be more carefully considered in translational proof-of-concept studies (Hermann et al. 2015). Indeed, vascular aging and endothelial dysfunction increase the susceptibility to and severity of ischemic stroke, emphasizing the role of oxidative stress and inflammatory responses in this process (Liu et al. 2024a, b).

Neurovascular remodeling in the aged brain after cerebral ischemia

The blood–brain barrier (BBB) is a selective permeability barrier that regulates the movement of substances between the bloodstream and the central nervous system (CNS). In the aging brain, structural and functional changes in the BBB can lead to increased permeability, potentially contributing to neurodegenerative diseases and cognitive decline (Hussain et al. 2021).

During normal aging, several structural and functional changes occur in the blood–brain barrier (BBB), including endothelial dysfunction, pericyte loss, and disruption of tight junctions. Endothelial cells, which line the cerebral vasculature, are critical for BBB function. Aging impairs their integrity, leading to increased BBB permeability and the potential entry of harmful substances into the brain (Andjelkovic et al. 2023). Pericytes, contractile cells that envelop endothelial cells in capillaries and venules, play an essential role in maintaining BBB stability. Age-related reductions in pericyte coverage contribute to BBB breakdown and elevated vascular permeability (Cummins et al. 2024). Similarly, tight junctions between endothelial cells, which are vital for preserving BBB integrity, are disrupted with age, further compromising barrier function and promoting neuroinflammatory processes (Denkinger et al. 2024).

BBB disruption is also a key feature of ischemic brain injury and hemorrhagic transformation. Increased permeability facilitates the infiltration of immune cells and pro-inflammatory mediators into the brain parenchyma, potentially triggering chronic neuroinflammation—a known risk factor for neurodegenerative diseases (Yusuf et al. 2022). Recent research has explored the use of plasma biomarkers to predict hemorrhagic transformation, elucidated novel mechanisms underlying BBB damage, and examined the therapeutic potential of stem cell-based interventions for stroke. These advancements contribute to a deeper understanding of BBB protection strategies in the context of stroke treatment (Chen et al. 2022). An overview of morphological changes in the neurovascular unit during aging and cerebral ischemia is provided in Fig. 1.

Fig. 1.

Fig. 1

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Overview of the structural changes in the neurovascular unit in the ageing brain and post-stroke brain. Figure created using BioRender

Angiogenesis after ischemic stroke

Angiogenesis, the formation of new blood vessels, is a critical component of brain repair following ischemic stroke. In the aged brain, angiogenesis is often impaired, leading to insufficient blood supply to the affected areas. Recent reviews have summarized the cellular and molecular mechanisms affecting angiogenesis after cerebral ischemia, providing insights into pro-angiogenic strategies for exploring therapeutic interventions (Fang et al. 2023).

Neuroinflammation in aging and cerebral ischemia

Neuroinflammation plays a pivotal role in both aging and cerebral ischemia, albeit with distinct characteristics and implications. In the aging brain, neuroinflammation is a fundamental mediator of cellular senescence within the central nervous system, contributing to the progression of neurodegenerative diseases and cognitive decline. This chronic, low-grade inflammation is marked by the activation of microglia and astrocytes, leading to the release of pro-inflammatory cytokines and reactive oxygen species, which can damage neuronal structures and function (Yousefzadeh et al. 2021). Conversely, cerebral ischemia induces an acute inflammatory response characterized by the rapid activation of microglia and the infiltration of peripheral immune cells into the brain parenchyma (Beuker et al. 2022). This response aims to contain and repair the ischemic injury but can also exacerbate neuronal damage if dysregulated. Recent studies have highlighted that aging can modify the neuroinflammatory response to cerebral ischemia. For instance, aged individuals exhibit elevated levels of inflammatory factors such as IL-1β, IL-6, TNF-α, and IFN-γ in brain tissue and peripheral blood following stroke, which are associated with poorer outcomes. Additionally, aging increases microglial proliferation and delays cell migration, potentially impairing the brain’s ability to effectively respond to ischemic injury. These findings underscore the complex interplay between age-related neuroinflammation and the brain’s response to ischemic events, suggesting that therapeutic strategies targeting neuroinflammatory pathways may need to be tailored differently for aging populations (Popa-Wagner et al. 2007; Yusuf et al. 2022; Chen et al. 2024).

One of the key challenges in the aged brain is the reduced capacity for neurogenesis, angiogenesis, and axonal sprouting, crucial processes for repair post-ischemia (Moraga et al. 2015; Apple et al. 2017). For instance, while younger brains can stimulate neurovascular niches that encourage angiogenesis after ischemic damage, this ability declines with age, making recovery slower and less effective (Petcu et al. 2010; Parambath et al. 2025; Alaqel et al. 2025). Additionally, the blood–brain barrier (BBB), vital for maintaining brain homeostasis, is more vulnerable to disruption during ischemia in aged brains. This leads to exacerbated neuronal injury and neurodegeneration, further limiting recovery (Chen et al. 2022).

Despite these challenges, certain molecular pathways offer hope for enhancing neuroplasticity and brain regeneration, even in older brains. Notably, signaling pathways such as Wnt/β-catenin, mTOR, and Notch have been identified as potential therapeutic targets. Activation of the Wnt/β-catenin pathway, for example, has been shown to promote tissue regeneration and synaptic plasticity, even in aged brains. The mTOR pathway, which regulates cellular growth and metabolism, also plays a significant role in promoting neuroplasticity and could be a promising target for interventions to enhance recovery post-stroke (Forouzanfar et al. 2022; Melanis et al. 2023; Khan et al. 2025).

Stem cell therapy for stroke: insights from animal models and clinical applications

Stem cell therapy has emerged as a promising strategy for stroke treatment, aiming to repair damaged brain tissue and restore neurological function. Various types of stem cells—most notably mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSCs), and neural stem cells (NSCs)—have demonstrated therapeutic potential in preclinical studies targeting both stroke and brain aging.

Among these, MSCs, particularly those derived from bone marrow or adipose tissue, are favored due to their neuroprotective properties, low immunogenicity, and minimal tumorigenic risk. In addition to direct stem cell transplantation, extracellular vesicles (EVs) derived from MSCs or blood plasma are emerging as potent therapeutic agents. These EVs may recapitulate many of the benefits of stem cell therapy while avoiding some associated risks (Doeppner et al. 2017; Rudnitsky et al. 2024).

MSCs and their derived EVs have also shown promise in promoting longevity and mitigating age-related diseases. Notably, the therapeutic efficacy of MSCs in humans appears to be relatively independent of donor age—a contrast to findings in rodent models. Systemic administration of MSCs or EVs derived from stem cells or plasma has been shown to rejuvenate the molecular (omic) profiles of various organs in aged rodents, shifting them towards a more youthful state (Rudnitsky et al 2025).

MSCs, derived from bone marrow or adipose tissue, have been investigated for their ability to promote neuroprotection and neuroregeneration. Studies indicate that MSCs can enhance neurogenesis, angiogenesis, and synaptogenesis, contributing to functional recovery post-stroke. For instance, intravenous administration of human bone marrow-derived MSCs has shown potential in repairing liver tissue and improving cardiac function in animal models, suggesting broader therapeutic applications (Nagaya et al. 2004; Liu et al. 2024a, b; Guan et al. 2025).

Similar to immune cells, mesenchymal stem cells (MSCs) can undergo functional polarization into either a pro-inflammatory phenotype (MSC1) or an anti-inflammatory phenotype (MSC2), depending on stimulation via Toll-like receptor 4 (TLR4) or Toll-like receptor 3 (TLR3), respectively. Systemically administered anti-inflammatory MSCs significantly reduced circulating levels of aging-associated chemokines in 18-month-old mice. This intervention also promoted hippocampal neurogenesis. Behaviorally, mice receiving MSCs polarized toward the MSC2 phenotype exhibited enhanced cognitive performance in both the Morris water maze and Y-maze tasks, compared to those treated with either vehicle or unpolarized (naïve) MSCs (Tfilin et al. 2023).

Muse cells, a naturally occurring subpopulation of pluripotent-like, non-tumorigenic stem cells isolated from human skin fibroblasts or bone marrow mesenchymal stem cells via the SSEA-3 surface marker, were shown to spontaneously and preferentially differentiate into neuronal lineages when transplanted into rodent models of stroke. Whether delivered stereotactically into the infarcted cortex or intravenously at subacute and chronic stages, Muse cells exhibited long-term survival in the host brain, with a large proportion differentiating into mature neurons expressing NeuN, MAP2, and other neuronal markers, while contributing minimally to glial lineages. Notably, the transplanted Muse cells not only engrafted within peri-infarct regions but also extended neurites across the pyramidal tract and spinal cord, re-establishing disrupted circuitry and forming anatomical and functional connections with host neurons. This neuronal integration was accompanied by significant and sustained improvements in motor and neurological functions, which were reversed upon targeted ablation of human cells, thereby confirming the direct contribution of Muse cells to recovery. Importantly, no tumor formation or ectopic tissue growth was observed up to 10 months post-transplantation, attesting to their safety. These findings collectively highlight the unique capacity of Muse cells to respond to the neurogenic cues of the injured brain microenvironment, differentiate robustly into neurons, and reconstruct damaged neural circuits, positioning them as a highly promising candidate for cell-based regenerative therapies in stroke and other neurodegenerative conditions. These studies underscore the significant therapeutic potential of multilineage-differentiating stress-enduring (Muse) cells in promoting neural regeneration following ischemic stroke. (Uchida et al. 2016, 2017; Abe et al. 2020).

Advances in subcellular approaches for stroke treatment

Recent research has highlighted the therapeutic potential of stem cell-derived exosomes in addressing neuroinflammation and cerebral ischemia, particularly in the context of aging. Exosomes, nanoscale extracellular vesicles secreted by stem cells, facilitate intercellular communication and carry bioactive molecules such as proteins, lipids, and RNAs. These properties make them promising candidates for treating age-related neurodegenerative conditions (Ma et al. 2024a, b).

MSC-sEVs and neuroprotection

Several studies have highlighted the promising role of MSC-derived small EVs (MSC-sEVs) as a potential treatment for ischemic stroke. These vesicles carry a range of bioactive molecules, including proteins and microRNAs, which can influence various cellular processes involved in stroke recovery. MSCs cultured under hypoxic conditions appear to produce more effective sEVs in promoting recovery, with these vesicles showing enhanced abilities to reduce ischemic brain injury, promote angiogenesis, and improve motor coordination in animal models (Gregorius et al. 2021; Xin et al. 2023; Surugiu et al. 2023).

One of the most consistent findings is the ability of MSC-sEVs to reduce inflammation in the brain. This includes a reduction in the infiltration of leukocytes (such as polymorphonuclear neutrophils, monocytes, and macrophages) into ischemic brain tissue. The studies suggest that MSC-sEVs modulate the inflammatory response, which is a critical factor in post-stroke damage. In particular, the reduction in the number of brain macrophages and microglia in the peri-infarct region is a key mechanism by which MSC-sEVs reduce neuroinflammation (Xin et al. 2023; Qin et al. 2024). Likewise, exosomes derived from human umbilical vein endothelial cells alleviated ischemia–reperfusion-induced brain injury by suppressing neuroinflammation, highlighting their therapeutic promise in stroke recovery (Ma et al. 2024a, b). Emerging evidence highlights the potential of EVs, particularly exosomes derived from stem cells, as they carry bioactive molecules like microRNAs and proteins that enhance neurogenesis, reduce inflammation, and promote vascular repair without the risk of cellular grafting (Gregorius et al. 2021; Zhong et al. 2023).

Mechanisms of action underlying the therapeutic effects of MSC-sEVs

Emerging evidence indicates that MSC-sEVs exert therapeutic effects through several interrelated mechanisms that support tissue repair and functional recovery after brain injury.

One of the key mechanisms is the promotion of angiogenesis. MSC-sEVs contribute to microvascular remodeling, an essential process for restoring blood flow to ischemic brain regions. In particular, sEVs derived from hypoxia-preconditioned MSCs have been shown to enhance endothelial cell proliferation, migration, and tube formation in vitro. These effects translate in vivo to increased microvascular density and branching within ischemic brain tissue (Kang et al. 2025).

In addition to promoting vascular repair, MSC-sEVs regulate aquaporin-4 (AQP4) expression and cerebrospinal fluid (CSF) flow. Stroke often leads to the disruption of CSF circulation and the depolarization of AQP4 water channels in astrocytes. Preconditioned extracellular vesicles from hypoxia-exposed microglia can mitigate AQP4 depolarization, reduce cerebral edema, and improve CSF dynamics, thus enhancing neuroprotection (Qin et al. 2024).

MSC-sEVs also influence microglial polarization, encouraging a shift from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 state. This modulation of microglial activation fosters an environment conducive to tissue repair and reduces secondary inflammatory damage (Qin et al. 2024).

Furthermore, MSC-sEVs promote neurogenesis, particularly within the subventricular zone, a key neurogenic niche following stroke. This enhancement of neuronal regeneration complements their anti-inflammatory and angiogenic effects, further supporting functional recovery (Kang et al. 2025).

Finally, MSC-sEVs play a role in modulating neuroinflammation and apoptosis through microRNA-mediated pathways. Recent studies have shown that encapsulating MSCs in a hydrogel matrix amplifies their therapeutic efficacy by promoting neovascularization, supporting neuronal differentiation, and suppressing neuroinflammation via regulation of apoptosis-related proteins (Liu et al. 2019; Wang and Liu 2021; Salimi et al. 2023).

Age-dependent effects of stroke therapies

Notably, some studies specifically address the challenges of treating stroke in aged rodents. While aged animals typically show more severe neurological deficits, larger infarct volumes, and a stronger inflammatory response than their younger counterparts, MSC-sEVs were still effective in promoting functional recovery and reducing neuroinflammation. The studies suggest that MSC-sEVs can improve motor coordination and reduce macrophage infiltration in older animals, demonstrating their potential for treating stroke in older populations, who are at higher risk of stroke and generally show worse recovery outcomes (Wang et al. 2022a, b; Dumbrava et al. 2022; Abuzan et al 2025).

Age is a critical determinant of stroke outcome, with older patients consistently exhibiting worse prognoses compared to their younger counterparts. Several studies have demonstrated that advanced age is independently associated with increased mortality, greater neurological disability, and reduced likelihood of functional recovery after stroke (Main et al. 2023). For instance, research from the Stroke Unit Trialists’ Collaboration highlights that patients over 75 years have significantly poorer outcomes than those under 55, even when receiving similar standards of care (Langhorne 2021). Furthermore, a population-based study showed that younger stroke patients (aged 18–45) were more likely to regain functional independence (modified Rankin Scale ≤ 2) at 3 months post-stroke than older adults, especially those over 70 or 80, who often face prolonged hospitalization, higher rates of institutionalization, and increased risk of recurrent strokes. These disparities underscore the impact of age-related physiological decline, increased comorbidities, and diminished neuroplasticity in older individuals, emphasizing ageing as the most significant unmodifiable risk factor influencing stroke recovery (Varona et al. 2004; Saposnik et al. 2008; Moosa et al. 2023; Varona et al. 2007).

Mitochondrial engineering as a therapeutic strategy in aging and disease

Mitochondrial dysfunction plays a pivotal role in aging and the pathophysiology of ischemic stroke (Bartman et al. 2024; Zhao et al. 2024). Upon stroke, the interruption of blood flow leads to oxygen and glucose deprivation, resulting in impaired mitochondrial function and energy deficits in brain cells. This dysfunction contributes to the generation of reactive oxygen species (ROS), which further damage cellular components and promote cell death. Additionally, mitochondrial permeability transition pore (mPTP) opening has been implicated in neuronal injury following ischemic events (Sanderson et al. 2013; Yang et al. 2021; Robichaux et al. 2023; Gao et al. 2024).

Mitochondrial transplantation is emerging as a promising therapeutic strategy for addressing mitochondrial dysfunction and age-related conditions—such as neurodegenerative diseases, cardiovascular aging, and reproductive decline—highlighting its potential for clinical application (Zhao et al. 2024).

Recent research has explored therapeutic strategies targeting mitochondrial health to mitigate stroke-induced damage. Engineered mitochondrial transplantation, which involves the transfer of healthy mitochondria to damaged cells, is a promising new strategy for treating mitochondrial dysfunction and aging-associated diseases. It has shown potential in restoring mitochondrial function and enhancing cell survival (Evan et al. 2023; Wang et al. 2024; Court et al. 2024). For instance, research indicates that mitochondrial transplantation can improve cardiac function in patients with cardiovascular diseases by enhancing mitochondrial activity and reducing oxidative stress (Sun et al. 2023). Similarly, in the context of degenerative joint diseases, transferring healthy mitochondria has been shown to alleviate mitochondrial dysfunction, reduce oxidative stress, and decrease cell apoptosis, thereby promoting tissue repair (Luo et al. 2024). Additionally, studies have explored the use of stem cell-derived mitochondria for transplantation, highlighting their potential in rescuing injured tissues and restoring mitochondrial function (Wang et al. 2018). Furthermore, interventions aimed at modulating mitochondrial dynamics—such as fusion and fission processes—are under investigation for their potential to improve outcomes after stroke (Zhou et al. 2021; Huang et al. 2023). However, while these findings are promising, further research and clinical trials are necessary to fully understand the efficacy and safety of mitochondrial transplantation in human patients.

Considerations, obstacles and challenges in stem cell therapy

Stem cell therapies hold significant promise for stroke treatment, yet several critical challenges must be overcome before they can be widely implemented in clinical practice. A major obstacle lies in the variability of stem cell sources. For instance, mesenchymal stem cells (MSCs) often exhibit heterogeneity due to donor-specific factors and differing isolation techniques, which can lead to inconsistent therapeutic outcomes and hinder reproducibility and efficacy (Kirkeby et al. 2025).

Another pressing concern is the potential tumorigenicity associated with certain cell types, particularly induced pluripotent stem cells (iPSCs). These cells possess high proliferative capacity and are prone to genetic instability, raising the risk of tumor formation. To address this issue, it is essential to ensure the complete and stable differentiation of iPSCs prior to transplantation (Garitaonandia et al. 2016; Boltze et al. 2019).

Immune rejection also poses a significant barrier, even in autologous cell therapies. The immunogenic nature of transplanted cells, especially those derived from iPSCs, can trigger adverse immune responses (Zhao et al. 2011; Aron Badin et al. 2019; Bogomiakova et al. 2023). Therefore, effective strategies to enhance immune tolerance and reduce immunoreactivity are required.

The lack of standardized manufacturing processes further complicates clinical translation. Inconsistent protocols for cell production, expansion, and quality control hinder scalability and regulatory approval. Establishing uniform and reliable production standards is imperative for ensuring safety and reproducibility (Garitaonandia et al. 2016; Boltze et al. 2019).

Moreover, the hostile environment of the post-stroke brain—characterized by inflammation, oxidative stress, and glial scarring—poses substantial challenges for cell survival, integration, and functional recovery. Enhancing the resilience of transplanted cells and promoting their effective integration into neural circuits are essential for achieving therapeutic benefit (Mohamed et al. 2024).

In addition to these biological and technical barriers, regulatory hurdles and the scalability of cell production remain major concerns that must be addressed. Robust preclinical studies and well-designed clinical trials are needed to tackle these multifaceted challenges and unlock the full therapeutic potential of stem cell-based interventions for stroke.

Despite encouraging preclinical findings, clinical trials on stem cell therapies for stroke have yielded mixed results regarding their safety and efficacy. While some studies have reported improvements in neurological function and quality of life, others have shown limited benefits. This variability may be attributed to differences in timing of administration, route of delivery, and patient-specific factors (Cha et al. 2024).

Blood–brain barrier (BBB) penetration

The BBB remains a significant obstacle in treating ischemic brain injury, as it limits the effectiveness of many therapeutic agents. Stem cell-derived exosomes show promise due to their ability to cross the BBB, making them a potential vehicle for delivering therapeutic agents to the brain (Borlongan et al. 2024).

Safety and efficacy of delivery routes

The safety profile of stem cell delivery varies by route. Intravenous (IV) administration is generally considered safe but may induce systemic side effects. In contrast, intracerebral injection enables localized delivery but carries higher risks, such as infection and tissue injury. Clinical trials continue to evaluate optimal delivery routes to balance therapeutic benefit and procedural risk (Borlongan et al. 2024).

Dosage and timing

The therapeutic efficacy of stem cell interventions is highly dependent on dosage and timing. Preclinical and clinical studies have explored various dosing regimens to identify protocols that maximize functional recovery (Vahab et al. 2024).

Stem cell administration routes

Intravenous injection

In preclinical models, IV injection is widely used for its simplicity and systemic distribution. Studies have shown that IV delivery of mesenchymal stem cells (MSCs) reduces infarct size and improves functional outcomes in rodent stroke models (Xu et al. 2024). Clinically, IV infusion of MSCs has been investigated for promoting neurovascular remodeling and functional recovery in acute ischemic stroke. A Phase 1/2 trial assessed the safety and efficacy of intravenously administered allogeneic MSC-derived exosomes in this context (Dehghani et al. 2021).

Stem cell-derived exosomes, particularly those from MSCs, have been administered intravenously in animal models to reduce neuroinflammation and promote repair in ischemic stroke (Liu and Jia 2024). Clinical trials have also explored this route, with evidence suggesting that IV infusion of MSC-derived exosomes may improve neurological outcomes in acute stroke patients (Xu et al. 2024).

Intranasal administration

This non-invasive route facilitates direct brain delivery via the olfactory and trigeminal nerve pathways, potentially bypassing the BBB. In animal models, intranasal delivery of MSC-derived exosomes has improved cognitive function and reduced ischemic injury (Cha et al. 2024; Dehghani et al. 2022). Although clinical application remains limited, early investigations are evaluating its feasibility and potential benefit in humans. Intranasal delivery of exosomes has shown neuroprotective and functional benefits in preclinical stroke models, leveraging direct access to the brain via neural pathways (Cha et al. 2024; Dehghani et. al. 2022). Clinical studies are ongoing, but current data remain limited.

Intracerebral injection

Direct brain injection offers precise delivery to the ischemic region and has been used in preclinical studies to promote neurogenesis and functional recovery (Dehghani et al. 2022).

In experimental models, intracerebral administration of exosomes allows for targeted delivery to the lesion site, promoting tissue repair and neuroprotection (Tatarishvili et al. 2014; Liu and Jia 2024). Clinically, this approach is used sparingly due to the high risks associated with invasive procedures. A summary of current administration routes is provided in Fig. 2.

Fig. 2.

Fig. 2

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Major routes of administration of cells, subcellular components, and drugs in cerebrovascular diseases. Figure created using BioRender

Several alternative administration routes have also been explored in both preclinical and clinical contexts. Intraperitoneal (IP) delivery of mesenchymal stem cells (MSCs) has demonstrated potent systemic immunomodulatory effects, including attenuation of experimental colitis and autoimmune arthritis. These effects are mediated through mechanisms such as the induction of IL-10—producing regulatory B cells and the suppression of joint inflammation (Liu et al. 2022; Nam et al. 2018). Similarly, intramuscular (IM) delivery of placental stromal cells has shown promise in mitigating systemic damage, such as radiation syndrome, by leveraging local tissue niches to support sustained cell viability and paracrine signaling (Gaberman et al. 2013). Intra-arterial (IA) administration has been investigated as a minimally invasive approach to directly target widespread neurodegeneration in large animal models; however, this route carries significant risks. Reports of microvascular obstruction and cerebral lesions, without consistent functional benefits, underscore the need for caution in cerebrovascular applications (Malysz-Cymborska et al. 2021; Argibay et al. 2017). Alternatively, subcutaneous (SC) delivery has gained attention for the treatment of localized conditions. SC injection of MSCs into inflamed or injured tissues has been shown to induce lymph node-mediated immunoregulation and promote tissue preservation and repair, as demonstrated in models of skin inflammation, burn injury, and phase I trials for psoriasis treatment(Zheng et al. 2024; Öksüz et al. 2013; Bajouri et al. 2023). Overall, while invasive routes such as IA offer direct access to the CNS, growing evidence supports the therapeutic potential of systemic (IP, IM) and local (SC) administration routes, particularly for targeting peripheral or immune-mediated components of neurobiological disease.

Conclusions

With aging, the brain undergoes a spectrum of molecular and cellular transformations that affect its structure and functionality, contributing to age-related disorders, particularly cerebrovascular conditions and a diminished ability to regenerate following ischemic injury. Although substantial research has been conducted, effective therapeutic interventions to promote brain rewiring and restore function after cerebral ischemia remain elusive. Gaining deeper insights into the cellular and molecular mechanisms that govern the post-acute stroke phase could pave the way for novel therapeutic strategies targeting vascular aging.

Recent progress has highlighted several areas of interest, including epigenetic modifications in the vascular wall, blood–brain barrier remodeling, advancements in cellular and subcellular therapies, and innovative delivery methods. Among these, stem cell-derived exosomes have emerged as a promising, cell-free approach to alleviate neuroinflammation and support recovery in age-related neurological disorders. Despite encouraging outcomes in preclinical studies, clinical trials have yielded inconsistent results regarding the safety and efficacy of cell-based therapies for stroke. This underscores the need for a comprehensive, multistage therapeutic strategy. Consequently, further investigation and rigorously designed clinical trials are essential to evaluate the potential and safety of mitochondrial transplantation in human patients.

Author contributions

Concept and design: Aurel Popa-Wagner, Dirk M Hermann, Raphael Guzman; Methodology: Roxana Surugiu, Denissa Greta Olaru, Bogdan Capitanescu; Writing and editing: Aurel Popa-Wagner, Dirk M Hermann, Bogdan Capitanescu; Funding acquisition: Aurel Popa-Wagner, Dirk M Hermann; Resources: Aurel Popa-Wagner, Dirk M Hermann; Supervision: Aurel Popa-Wagner, Dirk M Hermann. The first draft of the manuscript was written by Aurel Popa-Wagner, Denissa Greta Olaru, Bogdan Capitanescu and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

This work was supported by European Union via PNRR, “Targeting macrophages/monocytes in the aged ischemic brain by pharmacological, genetic and cell-based tools”, 760058/23.05.2023 to DHM. The Article Processing Charges were funded by the Doctoral School of the University of Medicine and Pharmacy of Craiova, Romania.

Data availability

No new data were generated or analyzed in support of this research.

Declarations

Conflicts of interest

No conflicts of interest to declare

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Bogdan Capitanescu and Dirk M. Hermann have contributed equally to this study.

Contributor Information

Denissa Greta Olaru, Email: denissagretaolaru@gmail.com.

Aurel Popa-Wagner, Email: aurel.popa-wagner@geriatrics-healthyageing.com.

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