How neural stem cell therapy promotes brain repair after stroke

 What is your doctor's protocol after reading all this research? Oh, your doctor doesn't plan on creating protocols? Why hasn't s/he been fired yet? Because the board of directors is also fucking incompetent?

FYI. This "Paracrine Effect" a better explanation than my earlier belief that exosomes were the reason for benefits from stem cells.

Application of stem cell-derived exosomes in ischemic diseases: opportunity and limitations

 The "Paracrine Effect" is the best thing about Stem Cells

The latest here:

How neural stem cell therapy promotes brain repair after stroke

Rebecca Z. Weber^1,2 ∙ Ruslan Rust^3,4 ∙ Christian Tackenberg^1,2 christian.tackenberg@irem.uzh.ch

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Summary

The human brain has a very limited capacity for self-repair, presenting significant challenges in recovery following injuries such as ischemic stroke. Stem cell-based therapies have emerged as promising strategies to enhance post-stroke recovery. Building on a large body of preclinical evidence, clinical trials are currently ongoing to prove the efficacy of stem cell therapy in stroke patients. However, the mechanisms through which stem cell grafts promote neural repair remain incompletely understood. Key questions include whether these effects are primarily driven by (1) the secretion of trophic factors that stimulate endogenous repair processes, (2) direct neural cell replacement, or (3) a combination of both mechanisms. This review explores the latest advancements in neural stem cell therapy for stroke, highlighting research insights in brain repair mechanisms. Deciphering the fundamental mechanisms underlying stem cell-mediated brain regeneration holds the potential to refine therapeutic strategies and advance treatments for a range of neurological disorders.

Keywords

1. iPS cells
2. neural progenitor cells
3. neural stem cells
4. ischemic stroke
5. cell therapy
6. brain regeneration

Introduction

Repair and regeneration of damaged organs is a fundamental principle for the survival of any organism. Generally, this is accomplished through two interdependent processes: (1) the dead tissue must be replaced by newly generated cells, and then (2) new cells must differentiate and become organized in complex patterns to restore the original structure and function of the injured organ. In humans, the repair properties may vary considerably between different organs. Some tissues, such as skin and liver, have strong endogenous cell replacement and pattern repair capabilities. In contrast, others, including the central nervous system (CNS), show only low regenerative potential (Chen et al., 2022). This is particularly problematic for patients suffering from brain disorders and injuries.

The most common cause of severe brain damage is ischemic stroke, yearly affecting over 13.7 million people and one in four people over age 25 in their lifetime (GBD 2016 Stroke Collaborators, 2019). An ischemic stroke typically occurs when an artery that supplies blood to the brain becomes blocked by a blood clot or plaque. If the blockage cannot be resolved with acute treatment, deficiency of oxygen and nutrients may rapidly cause severe brain damage or death. For each hour that treatment does not occur, the brain loses as many neurons as in 3.6 years of aging (Saver, 2006), and although other cell types within the stroke core are less sensitive to ischemia, they all eventually degenerate within a few hours following the infarct. Surrounding the stroke core, the peri-infarct zone consists of functionally impaired yet still viable tissue. Within the peri-infarct region, microglia become activated, and peripheral immune cells including neutrophils and macrophages are recruited through endothelial cells across the blood-brain barrier (BBB) minutes following the injury. The pro-inflammatory state promotes cytokine release, formation of reactive oxygen species, and extracellular matrix disruption. Astrocytes are activated days following the injury and produce cytokines and proteoglycans, the main component of the glial scar (Weber et al., 2022). These three cell types contribute to the secondary damage but also remodel the extracellular matrix and generate signals for neural repair. Absence of both inflammation and scar-forming processes has been associated with poor stroke recovery in preclinical models (Liddelow and Barres, 2016). In the later phases, within weeks to months, low levels of endogenous remodeling and regenerative processes take place, including angiogenesis, neurogenesis, and axonal sprouting. Primary functional recovery usually occurs within the first 3 months but can continue up to 3 years following stroke (Belagaje, 2017). As time is an extraordinarily critical factor, the primary aim in clinical practice is to restore blood flow as soon as possible through enzymatic or mechanical removal of the blood clot. Currently, the only treatment option of acute ischemic stroke patients is to restore blood flow by reperfusion therapy (Figure 1). The sole authorized drug available for treatment is the recombinant human tissue plasminogen activator alteplase. Although numerous randomized controlled trials and more than 25 years of clinical use have shown that intravenous administration of alteplase reduces disability in patients who experienced an acute ischemic stroke (Emberson et al., 2014), the relatively short treatment window narrows down its application since reperfusion therapies are only efficient until affected neural tissue is lost, and the infarct transits from the acute to the chronic phase (Grøan et al., 2021).

Figure 1 Existing and future options to treat ischemic stroke

Cell therapy is emerging as a promising and novel treatment paradigm for stroke, which has also been recognized by the Stroke Treatment Academic Industry Roundtable (Liebeskind et al., 2018). Notably, cell therapy in stroke has already reached the translational stage, with 30 (active or completed) clinical trials and therapeutic results in humans (Negoro et al., 2019). The safety of cell therapies in stroke has been demonstrated, further confirming the potential of this approach. However, efficacy of these therapies still needs to be confirmed in human subjects, and more work is needed to optimize stem cell application in clinical practice (Rust and Tackenberg, 2022).

This review compiles evidence from various preclinical studies, focusing on how stem cells, especially neural stem and progenitor cells (NSCs and NPCs), contribute to brain repair after stroke, and examines the mechanisms driving stem cell-based brain regeneration.

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