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October 17, 2025Open Access

Advancements in Hematopoietic Stem Cell Therapy: From Biological Pathways to Emerging Therapeutic Strategies

VCViviana CortianaUniversity of Perugia HCHarshal ChoryaSir Sayajirao General Hospital Medical College RARabab Hunaid AbbasTbilisi State Medical University

Key Points

Significant insights into HSC biology were gained through single-cell RNA sequencing, revealing critical regulatory mechanisms.
Zebrafish models provided unique views on HSC interactions with embryonic macrophages, impacting transplantation success.
The review discusses mutations in epigenetic regulators, linking clonal hematopoiesis to increased risks of hematologic disorders.
Emerging technologies like CRISPR-Cas9 are being explored to enhance HSC therapies and improve clinical outcomes.

Abstract

Hematopoietic stem cell (HSC) therapy remains essential in treating blood disorders, autoimmune diseases, neurodegenerative conditions, and cancers. Despite its potential, challenges arise from the inherent heterogeneity of HSCs and the complexity of their regulatory niche. Recent advancements in single-cell RNA sequencing and chromatin accessibility sequencing have provided deeper insights into HSC markers and chromatin dynamics, highlighting the intricate balance between intrinsic and extrinsic regulatory mechanisms. Zebrafish models have emerged as valuable tools in HSC research, particularly through live imaging and cellular barcoding techniques. These models have allowed us to describe critical interactions between HSCs and embryonic macrophages, involving reactive oxygen species and calreticulin signaling. These are essential for ensuring HSC quality and proper differentiation, with implications for improving HSC transplant outcomes. Furthermore, the review examines clonal hematopoiesis, with a focus on mutations in epigenetic regulators such as DNMT3A, TET2, and ASXL1, which elevate the risk of myelodysplastic syndromes and acute myeloid leukemia. Emerging technologies, including in vivo cellular barcoding and CRISPR-Cas9 gene editing, are being investigated to enhance clonal diversity and target specific mutations, offering potential strategies to mitigate these risks. Additionally, macrophages play a pivotal role in maintaining HSC clonality and ensuring niche localization. Interactions mediated by factors such as VCAM-1 and CXCL12/CXCR4 signaling are crucial for HSC homing and the stress response, opening new therapeutic avenues for enhancing HSC transplantation success and addressing clonal hematopoiesis. This review synthesizes findings from zebrafish models, cutting-edge sequencing technologies, and novel therapeutic strategies, offering a comprehensive framework for advancing HSC biology and improving clinical outcomes in stem cell therapy and the treatment of hematologic diseases.

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