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Hematopoietic Stem Cell Transplantation (HSCT): What we can do to combat complications

Since the first successful non-twin (allogeneic) bone marrow transplant in 1968,¹HSCT has been used as the only cure for certain leukemias and other diseases, such as primary immunodeficiencies. Recently, the use of peripheral blood stem cells in autologous transplantation has been reported to be increasing. Compared with conventional bone marrow transplantation, peripheral blood stem cell transplantation is associated with lower treatment-regimen- and transplant-related mortality.²The steps of bone marrow and blood-derived HSCT are shown in Figure 1.

Figure 1. HSCT procedure (https://www.britannica.com/media/full/topic/240689/123191)

Although allogeneic hematopoietic stem cell transplantation has been highly successful, severe and sometimes life-threatening inflammatory complications can occur due to differences in major and minor transplantation antigens between donors and patients. Most of these complications, such as graft-versus-host disease (GVHD) and thrombotic vasculopathy (TMA), are caused by endothelial injury (damage to the lining cells of blood vessels). The pathway of endothelial injury that leads to hematopoietic stem cell transplantation causing TMA is shown in Figure 2. Ways to prevent transplant-related complications such as TMA need to be elucidated, and the clinical course of these complications is highly variable from patient to patient, necessitating personalized precision medicine.

Figure 2. Pathways of endothelial injury in TMA. Exogenous factors due to hematopoietic stem cell transplantation (HSCT). ²

As our group has previously shown, donor leukocytes specifically attack recipient endothelial cells. ³By culturing these donor leukocytes with laboratory-generated patient-specific endothelial cell lines, we aim to quantify the risk of endothelial injury for individual donor-recipient pairs in a pediatric patient cohort. The procedure to generate specific cell lines involves differentiating so-called mesenchymal stem cells (MSCs) from bone marrow into endothelial cells, which are then converted into robustly proliferating tissue culture cells. These culture experiments can be used to identify which patient-donor pairs are most likely to suffer severe endothelial injury. Based on this information, high-risk patient-donor pairs can be prescribed a prophylactic drug regimen to protect the endothelium during the transplant period.

We believe that this personalised medicine approach will result in higher outcome rates in both paediatric and adult patients. This research is funded by a grant from the National Childhood Research Centre, which enables us to work closely with clinicians at the Irish Centre for Child Health in Culmlin, Dublin.

Figure 3. A 4-year-old boy suffering from primary immunodeficiency disease waits in a special hospital bed for a hematopoietic stem cell transplant. (Photo: https://kknews.cc/zh-sg/health/kab885q.html)

When I was still a medical resident at Xiangya Hospital in Changsha, China, I saw many children suffering from immunodeficiency due to leukemia. They had to sleep in special hospital beds (Figure 3) because even a small infection can cause serious damage to their body. HSCT is a real hope for them. At that time, I never imagined that I would be able to earn a PhD in the field of stem cell therapy and immune responses to endothelial cells. Now, with this opportunity at UCD, I can contribute to this field and become a proud stem cell scientist.

Last but not least, stay calm and Stemmy will save the world!

References:

1. https://www.fredhutch.org/en/treatment/long-term-follow-up/FAQs/transplantation.html
2. Hosing, Chitra. “Hematopoietic stem cell mobilization by G-CSF.” Stem Cell Mobilization, pp. 37-47. Humana Press, Totowa, NJ, 2012.
3. Seaby, Eleanor G., and Rodney D. Gilbert. “Thrombotic microangiopathy after hematopoietic stem cell transplantation” Pediatric Nephrology33, No. 9 (2018): 1489-1500.
4. Eisner, Günther, Isabelle Hartmann, Artug Kesikli, Ernst Holler, Sylvia Hafner, Tanya Sachs, Carolyn Schrey, Bruno Meiser, and Bruno Reichardt. “CD4+ CD25+ FoxP3+ Regulatory T Cells Enhance the Alloactivity of Endothelial-Specific CD8+/CD28- CTLs.” International ImmunologyVolume 23, Issue 8 (2011): Pages 485-492.

Abbreviations:

CFH: Complement factor H

CFI: Complement factor I

GVHD: Graft-versus-host disease

HSCT: Hematopoietic stem cell transplantation

IL-1: Interleukin 1

ICAM-1: Intercellular adhesion molecule 1

MSC: Mesenchymal stem cells

MAC: Membrane attack complex

MPO: Myeloperoxidase

MCP: Membrane cofactor protein, also known as CD46

NETs: Neutrophil extracellular traps

PGI2: Prostaglandin I2

TMA: Thrombotic vasculopathy

TNF-α: Tumor necrosis factor alpha

TF: tissue factor

TxA2: Thromboxane A2

vWF: von Willebrand factor

VCAM-1: Vascular cell adhesion molecule 1