Endothelial cell dysfunction: a key determinant for the outcome of allogeneic stem cell transplantation

Abstract

Allogeneic hematopoietic stem cell transplantation (alloSCT) carries the promise of cure for many malignant and non-malignant diseases of the lympho-hematopoietic system. Although outcome has improved considerably since the pioneering Seattle achievements more than 5 decades ago, non-relapse mortality (NRM) remains a major burden of alloSCT. There is increasing evidence that endothelial dysfunction is involved in many of the life-threatening complications of alloSCT, such as sinusoidal obstruction syndrome/venoocclusive disease, transplant-associated thrombotic microangiopathy, and refractory acute graft-versus host disease. This review delineates the role of the endothelium in severe complications after alloSCT and describes the current status of search for biomarkers predicting endothelial complications, including markers of endothelial vulnerability and markers of endothelial injury. Finally, implications of our current understanding of transplant-associated endothelial pathology for prevention and management of complications after alloSCT are discussed.

Endothelial Dysfunction after Hematopoietic Stem Cell Transplantation: A Review Based on Physiopathology

“…A high level of Ang-2 persisting after first-line therapy is a marker of corticosteroid-refractory GVHD [176], and ED may explain gastrointestinal signs and symptoms in these patients. Luft hypothesized that endothelial cell vulnerability and dysfunction, rather than refractory T-cell activity, drive the pathophysiology of corticosteroid-refractory GVHD [22,176].…”

“…PRES is a neurologic disease characterized by brain edema, which is worsened by CSA treatment. It may be considered an endothelium disease of the vascular bed of the central nervous system [22].…”

Functions of the endothelium and its role in hematopoietic cell transplantation

“…As it is known, stem cell transplantation is an effective treatment method that can cure many diseases. However, approximately one-third of the patients die within 1 year after transplantation, especially due to problems encountered during or after allogeneic transplantation [44,45].…”

“…When the literature is reviewed, many risk factors are mentioned for complications due to endothelial dysfunction after HSCT. Conditioning regimen, use of TBI, type and number of transplants, lower performance, older age, degree of HLA mismatch, the presence of pretransplant comorbidities, and donor type are the most defined risk factors [45,47].…”

The Impact of NLRP3 Activation on Hematopoietic Stem Cell Transplantation

“…In a mouse model of HSCT busulfan and cyclophosphamide (often used in transplant conditioning regimens) induced liver inflammation through NLRP3 activation, and the pharmacological inhibition of NLRP3 reduced infiltration of macrophages and neutrophils and improved liver function [53], thus suggesting that targeting NLRP3 may have a therapeutic potential to prevent transplant complications, particularly in the prophylaxis of liver inflammation after HSCT. Moreover, inflammation and pyroptosis triggered by NLRP3 inflammasome activation play a crucial role in aggravating oxidative stress and endothelial dysfunction [13], and accumulating evidence indicates that endothelial dysfunction is involved in various complications of HSCT such as VOD, transplant-associated thrombotic microangiopathy, and refractory acute GvHD [54].…”