Sudheer Shenoy P.

The ontogenic development of hematopoietic stem cells (HSCs) occurs across diverse niches, with HSCs migrating from the aorta‐gonad‐mesonephros (AGM) to the fetal liver and finally residing in the bone marrow after birth, where adult HSCs replenish the hematopoietic system. The HSC niche critically regulates tropism and proliferation via factors secreted by the microenvironment interaction. Here, we hypothesized that HSCs display tropism toward the aggressive cancer stem cell (CSC) niches of triple‐negative breast cancer (TNBC) and MCF‐7 cells breast cancer, which exhibit high relapse rates and are potential targets for cell therapy. Our results demonstrate HSC‐specific tropism toward breast CSCs, leading to interactions that trigger HSC differentiation into CD4 ⁺ and CD8 ⁺ subpopulations within the cancer microenvironment. Proteomics of migrated HSCs toward TNBC‐CSCs/MCF‐7 cells revealed significant upregulation of IL‐7, Notch, and other proteins involved in T cell activation and migration pathways. Metabolomics of HSC‐conditioned medium (HSC‐CM)‐treated CSCs/MCF‐7 cells further demonstrated that HSC‐CM arrests TNBC‐CSC growth and cell cycle progression by altering the mitochondrial bioenergetics. This study highlights the potential of leveraging both HSCs and HSC‐derived factors for personalized therapies targeting CSCs in TNBC.

Prolonged glucocorticoid exposure leads to oxidative stress, mitochondrial damage and impaired myogenesis reducing the overall health of the skeletal muscles. Dexamethasone (dex), a synthetic glucocorticoid, induces proteolysis and inflammation by disrupting cellular energetics and mitochondrial function. Vitamin B3 (vit B3), an NAD⁺ precursor, is known to be a natural antioxidant and anti-inflammatory compound. This study investigates the protective role of vit B3 against dex-induced skeletal muscle damage, focusing on mitochondrial homeostasis and the IKK/FoxO3a signalling axis. C2C12 myoblasts were treated with dex (200 µM) and/or vit B3 (1 mM). Oxidative stress, mitochondrial potential and DNA damage was evaluated using DCFDA, JC1, and γH2AX immunostaining, respectively. Gene expression analysis was performed to assess the mitochondrial fission/fusion and the extent of electron transport chain (ETC) gene expression. Protein expression of inflammatory (IKKα/β, NFκB) and atrophy markers were analysed using immunoblotting and flow cytometry. The extent of myogenic differentiation was evaluated using MyoD and MyHC1 immunostaining along with measurement of the morphometric parameters. Vit B3 treatment significantly enhanced C2C12 viability and reduced dex-induced ROS production while restoring Nrf2 expression. It prevented DNA damage and preserved mitochondrial membrane potential. The results also implicated increased mitochondrial fusion upon vit B3 treatment as seen by the elevated gene expression of Mfn1, Mfn2 and Opa1 and decreased fission as observed by the reduced expression of Fis1 and Drp1. The NADH levels were also seen to be rescued by vit B3 supplementation which translates to better energy production by the electron transport system. Additionally, vit B3 was observed to suppress inflammation and prevent muscle proteolysis by modulating an IKK/FoxO3a axis. Finally, vit B3 was able to improve differentiation as seen by the levels of MyoD and MyHC1 expression in the cells. Vit B3 acts in a multifaceted manner and reduces dex-induced skeletal muscle atrophy which is primarily a result of reduced oxidative stress and restored mitochondrial homeostasis. These findings highlight vit B3 as a potential therapeutic and nutritional supplement for maintaining the skeletal muscle health under myopathic conditions.

Selective migration of tumors to particular organs, referred to as organ tropism, is not arbitrary but guided by intricate molecular interactions and a complex network of various secretory molecules. This site‐specific migration is modulated by molecular crosstalk, where cytokines and other effectors help tumor cells adapt to and colonize a new organ by reshaping their epigenetics. It is well established that breast and colorectal cancers, for instance, can epigenetically modify themselves to show a preference for the brain, bones, lungs, and liver but the key modulators are still elusive. Here, we have discussed the key mechanisms, including the critical interacting molecules, cytokines, and pathways that drive this site‐specific tropism‐based colonization. By synthesizing current knowledge, we highlight central players in this process and discuss their potential as therapeutic targets to inhibit metastasis and improve patient outcomes.

Mitochondria, often referred to as the “powerhouses of the cell,” are particularly crucial in cancer cells due to their high energy demands. Mitochondrial fusion-fission dynamics play a critical role in regulating signaling pathways and metabolic activities in colorectal cancer (CRC) cells. Increased mitochondrial fission drives metabolic reprogramming, enabling CRCs to proliferate, metastasize, and resist chemotherapy. Paradoxically, excessive fission induces mitochondria-mediated apoptosis. Our previous studies have shown that hematopoietic stem cell-derived conditioned media (CM) modulate the apoptosis pathway and mitochondrial bioenergetics of cancer stem cells by altering the cancer microenvironment. In this study, we found that HSCs-CM facilitates excessive fission in colorectal cancer cells by modulating Drp-1 and inducing the mitophagy-mediated apoptosis pathway, leading to the clearance of these cells. Moreover, proteomics data showed that HSCs-CM dysregulated the electron transport chain complexes, with an exceptionally high degree of dysregulation of complexes III and IV. Metabolomics and RNA sequencing revealed the dysregulation of critical proteins involved in mitochondrial bioenergetics and the autophagy pathway in CRCs treated with CM. Taken together, our studies reveal the therapeutic potential of HSC-conditioned media for treating colorectal cancer. Highlights: Hematopoietic stem cell-derived conditioned media induced excessive mitochondrial fission by upregulating the Drp-1 protein, leading to the upregulation of the apoptosis pathway and cell death. The excessive mitochondrial fission and bioenergetic dysfunction induced by HSCs-CM result in a loss of mitochondrial membrane potential (MMP) and high reactive oxygen species (ROS) production HSCs-CM severely disrupt mitochondrial bioenergetics in CRC cells, leading to an energy crisis and promoting the PINK-1 mediated mitophagy pathway.

Glucotoxicity or hyperglycemia as a consequence of Type 1 diabetes affects numerous tissues, including skeletal muscles, and translates to muscle wasting or atrophy. Since 40% of the total body weight comprises skeletal muscles, and because this tissue plays an essential role in voluntary movement, protecting its integrity is crucial for maintaining whole‐body homeostasis. Although different studies have investigated the role of arachidonic acid (AA) in salvaging skeletal muscle atrophy, the underlying mechanisms concerning the activation of muscle stem cells and the regenerative process need further elucidation. In this study, we use a streptozotocin‐induced Type 1 diabetes mouse model to study the effects of AA in mitigating the reduction in the myogenesis process and also try to elaborate on the anti‐atrophic and anti‐inflammatory properties of AA, which help to rescue the levels of sarcomeric protein. To carry out this study, male C57BL/6 mice (5‐week‐old) were divided into Control, diabetic (STZ) and AA‐administered diabetic (STZ + AA) groups ( n = 6 mice per group). The study involved a short‐term treatment regime of 5 days. Muscle stem cell activation, inflammation, and muscle fiber integrity were assessed using molecular techniques. A global proteomic study provided insights into differential protein expression status. Histological analysis revealed the rescue of muscle cells at different stages of myogenesis and fiber integrity upon AA administration in diabetic mice. Moreover, the proteomic results supported the upregulation of stemness upon AA treatment as well. Additionally, it also showed the rescue of the sarcomeric protein repertoire. The findings suggest that AA holds myogenic properties, which stem from its role in activating the muscle stem cells, and this can be used as a potential therapeutic supplement for diabetic patients.