Hematopoietic Stem Cell Tropism: Mechanisms Underlying Tropism to Cancer, Cancer Stem Cells, and Associated Metabolic Alterations.

Hematopoietic stem cells (HSCs) are essential for lifelong hematopoiesis, maintaining the body's diverse blood cell populations. Beyond this fundamental role, HSCs exhibit remarkable responsiveness to tissue damage and inflammation. They possess the capacity to mobilize from the bone marrow niche, migrate to sites of pathology, and contribute to tissue repair and regeneration processes.

A particularly significant and complex aspect of this migratory behavior is the observed tropism of HSCs towards cancerous lesions and cancer stem cells (CSCs). This phenomenon occurs within a tumor microenvironment characterized by significant metabolic reprogramming.

Key research questions driving this field include:

1. What are the precise molecular and cellular mechanisms governing HSC tropism specifically to tumors and CSCs?

2. Which specific chemoattractant signals, adhesion molecules, and microenvironmental cues drive this pathological tropism?

3. How do metabolic alterations within the tumor microenvironment, or within the HSCs themselves, influence their migratory behavior towards cancer

HSC-Conditioned Media Dysregulate Mitochondrial Dynamics in Colorectal Cancer

Colorectal cancer (CRC) relies on the balance of mitochondrial fission-fusion dynamics for survival and chemoresistance. While increased fission supports CRC progression, excessive fission triggers apoptosis. We demonstrate that hematopoietic stem cell-derived conditioned media (HSC-CM) shifts this balance, inducing pathological mitochondrial fission in CRC cells via DRP-1 activation and mitophagy. Here, we are exploring this molecular mechanism by various throughput techniques. 

Key Research Questions:

1. What specific factors in HSC-CM are responsible for inducing DRP-1-mediated fission and ETC dysregulation?

2. Does HSC-CM enhance the efficacy of standard chemotherapy in in vivo CRC models?

3. How does mitophagy induction selectively eliminate CSCs versus normal stem cells?

4. Can HSC-CM effects be replicated in other fission-dependent cancers (e.g., pancreatic, ovarian)?

5. Do metabolomic shifts in treated CRCs reveal actionable metabolic vulnerabilities?

Epigenetic Reprogramming of Hematopoietic Stem Cells in Type 1 Diabetes Pathogenesis

Type 1 Diabetes (T1D) involves systemic epigenetic dysregulation that alters hematopoietic stem cell (HSC) differentiation, favoring pro-inflammatory myeloid lineages while compromising lymphoid tolerance. This reprogramming is driven by:

1. Metabolic perturbations disrupting mitochondrial α-ketoglutarate/succinate ratios, which dysregulate TET/DNMT activity

2. Aberrant DNA methylation, histone modifications (e.g., H3K27me3), and noncoding RNA expression

Key Research Questions:

1. What specific chemoattractant signals drive HSC migration to pancreatic microenvironments in early T1D?

2. How do metabolic alterations in the bone marrow niche initiate epigenetic reprogramming of HSCs?

3. What distinct epigenetic signatures in HSCs precede myeloid/lymphoid skewing in T1D progression?

4. Do TET2/DNMT3A mutant HSC clones exhibit unique tropism or inflammatory profiles targeting pancreatic islets?

5. Can metabolic normalization reverse epigenetic dysregulation in HSCs to restore immune tolerance?

Exploiting CD34-ICAM1 Binding for Targeted Drug Delivery to Cancer Stem Cells using Hematopoietic Stem Cells

CD34-positive hematopoietic stem cells (HSCs) possess intrinsic tropism towards tumors and cancer stem cells (CSCs). We propose leveraging CD34+ HSCs as natural drug delivery vehicles to target CSCs in triple-negative breast cancer (TNBC). Through in silico screening of TNBC CSC-upregulated proteins, we identified ICAM1 as a high-affinity binding partner for CD34. In vitro validation confirmed a strong interaction between CD34 and ICAM1, establishing the feasibility of CD34+ HSC-mediated drug delivery specifically to ICAM1-overexpressing CSCs.

Key Research Questions:

1. Can CD34+ HSCs be efficiently loaded with anti-cancer therapeutics without compromising viability or tropism?

2. Does CD34-ICAM1 binding enhance targeted drug delivery and cytotoxicity against TNBC CSCs in vivo?

3. How do tumor microenvironment factors influence HSC homing efficiency to ICAM1+ CSCs?

4. Can this delivery platform overcome CSC-specific drug resistance mechanisms?

5. Is this strategy applicable to other ICAM1-overexpressing solid tumors beyond TNBC?

Modeling the tropism of hematopoietic stem cells (HSCs) toward triple-negative breast cancer (TNBC) cells.

Key Research Questions:

1. How do specific TNBC proteins differentially influence HSC chemotaxis, and are their effects additive or synergistic?

2. What is the timescale for HSC accumulation at TNBC sites, and how does it scale with protein expression gradients?