Ex vivoexpansion of cord blood-CD34⁺cells using IGFBP₂and Angptl-5 impairs short-term lymphoid repopulationin vivo

Abstract

Cord blood-derived haematopoietic stem cells (CB-HSCs) are an attractive source for transplantation in haematopoietic disorders. However, the yield of CB-HSCs per graft is limited and often insufficient, particularly for the treatment of adult patients. Here we compare the capacity of three cytokine cocktails to expand CB-CD34(+) cells. Cells were cultured for 5 or 14 days in media supplemented with: (a) SCF, FL, IL-3 and IL-6 (SFLIL3/6); (b) SCF, TPO, FGF-1 and IL-6 (STFIL6); and (c) SCF, TPO, FGF-1, IGFBP2 and Angptl-5 (STFAI). We observed that STFAI-culture expansion sustained the most vigorous cell proliferation, maintenance of CD34(+) phenotype and colony-forming unit counts. In addition, STFAI-cultured cells had a potent ex vivo migration activity. STFAI-expanded cells were able to engraft NSG mice. However, no significant difference in overall engraftment was observed among the expansion cocktails. Assessment of short-term reconstitution using multilineage markers demonstrated that the STFAI cocktail for HSCs expansion greatly improved total cell expansion but may impair short-term lymphoid repopulation.

Insulin-Like Growth Factor Binding Proteins in Autoimmune Diseases

“…IGFBP3 was also proved to support the development and maintenance of naïve CD8+ T cells, indicating the beneficial impact of IGFBP3 in maintaining a health immune system (103). IGFBP2 supplement can maintain vigorous hematopoietic cell expansion and CD34+ phenotype (104). …”

Angiopoietin-like proteins stimulate HSPC development through interaction with notch receptor signaling

“…Angiopoietin-like proteins (ANGPTLs) were recently identified as growth factors capable of expanding mouse ( Zhang et al, 2006 ; Zheng et al, 2011 ; Farahbakhshian et al, 2014 ) and human ( Zhang et al, 2008 ; Khoury et al, 2011 ; Ventura Ferreira et al, 2013 ; Fan et al, 2014 ) HSPCs in culture. ANGPTLs are secreted proteins that closely resembled the Angiopoietins, which are important vascular regulators, but despite structural similarities, they do not bind to TIE-2 or TIE-1 ( Kim et al, 1999 , 2000 ; Oike et al, 2004 ).…”

Author response: Angiopoietin-like proteins stimulate HSPC development through interaction with notch receptor signaling

“…Angiopoietin-like proteins (ANGPTLs) were recently identified as growth factors capable of expanding mouse (Zhang et al, 2006;Zheng et al, 2011;Farahbakhshian et al, 2014) and human (Zhang et al, 2008;Khoury et al, 2011;Ventura Ferreira et al, 2013;Fan et al, 2014) HSPCs in culture. ANGPTLs are secreted proteins that closely resembled the Angiopoietins, which are important vascular regulators, but despite structural similarities, they do not bind to TIE-2 or TIE-1 (Kim et al, 1999(Kim et al, , 2000Oike et al, 2004).…”