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Reactive oxygen species (ROS) have a dual nature in cellular activities, serving both beneficial and detrimental roles. At physiological levels, ROS act as crucial signaling molecules, participating in various cellular processes such as proliferation, differentiation, and apoptosis. They also play a vital role in immune responses and defense against pathogens. However, excessive ROS production can lead to oxidative stress, causing damage to cellular components and disrupting cellular homeostasis. Balancing ROS levels is therefore essential for maintaining cellular health and preventing diseases.

A research conducted by Huang et al. has unveiled a unique role of redox metabolism in acute myeloid leukemia (AML) pathogenesis. AML is a devastating hematological disorder characterized by the accumulation of immature myeloid cells in the bone marrow, leading to a depletion of normal blood cell production. AML remains a challenging disease due to its heterogeneity and the existence of leukemia-initiating cells (LICs), which are responsible for disease initiation, progression, relapse, and resistance to therapy. The researchers developed a highly sensitive and bright genetically encoded hydrogen peroxide (H₂O₂) sensor, named HyPerion, and engineered transgenic mice expressing this sensor. This powerful tool enabled them to monitor H₂O₂ levels in AML cells at single-cell resolution in vivo, providing unprecedented insights into the dynamic changes of redox metabolism during leukemogenesis.

Using HyPerion, the researchers discovered significant heterogeneity in H₂O₂ levels among AML cells. They identified a subset of AML cells with low H₂O₂ levels, termed HyPerion-low cells, which exhibited enhanced leukemogenic capacities and were enriched for functional LICs. These HyPerion-low cells displayed higher colony-forming ability, potent drug resistance, and a preference for localization in the endosteal niche of the bone marrow. Furthermore, they exhibited distinct metabolic features, relying more on glycolysis and less on oxidative phosphorylation compared to their HyPerion-high counterparts.

To elucidate the mechanisms underlying the maintenance of low H₂O₂ levels in HyPerion-low cells, the researchers conducted a comprehensive analysis of genes involved in ROS clearance and generation. They found that the expression of malic enzymes, including ME1 and ME3, was significantly upregulated in HyPerion-low cells. ME1 and ME3 mediate the conversion of malate to pyruvate, generating NADPH in the process. NADPH serves as a critical cofactor for the detoxification of H2O2, effectively reducing its levels within cells. Consistent with this finding, knockdown of ME1 or ME3 in AML cells led to an increase in H₂O₂ levels, decreased leukemogenic capacity, and impaired drug resistance.

The study further explored the connection between H₂O₂ levels and chemotherapy resistance in AML cells. They found that HyPerion-low cells were more resistant to the commonly used chemotherapeutic agent Ara-C. Treatment with Ara-C further increased the expression of ME1 and ME3 in HyPerion-low cells, suggesting a potential feedback loop promoting drug resistance.  Combining Ara-C with a ME inhibitor effectively delayed AML development in mice, highlighting the potential of targeting ME1/3 as a strategy to overcome chemotherapy resistance.

The researchers also extended their findings to human primary AML cells. They demonstrated that HyPerion-low cells were enriched for functional LICs and exhibited similar metabolic characteristics as observed in the murine model. These findings underscore the relevance of their discoveries to human AML and the potential clinical implications of targeting redox metabolism in leukemia treatment.

The potential of ROS modulation as a therapeutic tool extends beyond AML and into other areas of medicine, including hair growth. While ROS are often associated with oxidative stress and damage, controlled ROS generation and delivery can stimulate cellular processes crucial for hair follicle development and regeneration. This emerging field bridges the gap between redox biology and regenerative medicine, offering innovative approaches to address complex diseases like hair loss.

Current treatments like minoxidil and finasteride, while effective, require frequent application and can cause unwanted side effects. To address these limitations, researchers have explored alternative strategies, including the use of reactive oxygen species (ROS) to stimulate hair growth. Bai et al. introduced a novel approach called Materiobiomodulation Therapy (MBMT), which utilized polydopamine (PDA) nanoparticles to deliver ROS directly to hair follicle stem cells (HFSCs) and promote de novo hair growth.

The researchers harnessed the unique properties of PDA, a material with redox activity. By controlling the redox state of PDA nanoparticles, they could modulate their ROS generation capacity. The oxidized form (OXI) had minimal ROS production, while the reduced form (RED) released H2O2 upon exposure to oxygen. This allowed for precise control over the intracellular ROS level.

The team demonstrated that PDA nanoparticles could enter cells through clathrin-dependent endocytosis, bypassing the barrier of the cell membrane. This ensured high-efficiency delivery of ROS directly to the cytoplasm. Like Huang et al., the researchers also utilized HyPerion to monitor the intracellular H₂O₂ levels in real-time. This approach provided a dynamic and precise understanding of how PDA nanoparticles modulated the cellular redox environment.

Subcutaneous administration of PDA nanoparticles with controlled ROS generation significantly accelerated hair growth in mice. The treatment induced a rapid onset of the telogen-anagen transition (TAT), leading to the formation of new hair follicles. The researchers observed an increase in the number and density of anagen hair follicles, as well as enhanced expression of hair follicle markers like CD29 and CD34. These markers indicated the activation and proliferation of HFSCs, essential for hair growth.

The study investigated the dose-effect relationship of PDA nanoparticles on hair regrowth. They found that moderate levels of ROS were optimal for promoting hair growth, while excessive ROS had a detrimental effect. This phenomenon is consistent with the hormesis effect, where low levels of stressors can elicit beneficial responses. The researchers achieved precise control over the ROS level by adjusting the redox state and dosage of PDA nanoparticles.

To understand the underlying mechanism, the researchers performed transcriptomic analysis. They identified the Wnt/β-catenin signaling pathway as a key regulator of ROS-induced hair regrowth. PDA nanoparticles activated this pathway, leading to the upregulation of hair follicle markers and the promotion of hair growth. In contrast, excessive ROS suppressed the Wnt/β-catenin pathway, inhibiting hair growth.

To enhance the practicality of MBMT, the researchers developed a dissolving microneedle patch for transdermal ROS delivery. The patch contained PDA nanoparticles and hyaluronic acid, which allowed for controlled and sustained release of ROS upon insertion into the skin. The microneedle patch demonstrated similar efficacy to subcutaneous injection, promoting rapid hair growth without the need for professional assistance.

The MBMT approach represents a promising strategy for treating hair loss. PDA nanoparticles offer a unique solution for controlled and efficient ROS delivery, activating the Wnt/β-catenin signaling pathway and promoting hair follicle regeneration. The dissolving microneedle patch provides a convenient and user-friendly method for self-administration. Future research could focus on optimizing the PDA nanoparticles and exploring their potential in treating other skin-related conditions. The MBMT platform holds great promise as a next-generation therapeutic regimen for hair loss and beyond.

In summary, both studies demonstrated the importance of ROS in cellular processes, but their findings highlighted distinct roles and mechanisms within different systems. The development of the HyPerion sensor and its application in both studies provides valuable tools for studying the dynamic changes of ROS levels in various cell types.

Reference:

1. Huang D, Zhang C, Xiao M, Li X, Chen W, Jiang Y, Yuan Y, Zhang Y, Zou Y, Deng L, Wang Y, Sun Y, Dong W, Zhang Z, Xie L, Yu Z, Chen C, Liu L, Wang J, Yang Y, Yang J, Zhao Y, Zheng J. Redox metabolism maintains the leukemogenic capacity and drug resistance of AML cells. Proc Natl Acad Sci U S A. 2023 Mar 28;120(13):e2210796120.

2. Bai L, Wang Y, Wang K, Chen X, Zhao Y, Liu C, Qu X. Materiobiomodulated ROS Therapy for De Novo Hair Growth. Adv Mater. 2024 May;36(21):e2311459.