Going home: inhibiting stem cell CD26

Hal E. Broxmeyer

Comment on Peranteau et al, page 4268

Enhancing the homing and engrafting capability of hematopoietic stem cells (HSCs) would result in improved efficacy of HSC transplantation, especially when limiting numbers of donor cells are available.

The potential for HSC transplantation in utero (IUHCT) to correct congenital and genetic disorders before the harmful defects of the disorders are clinically apparent has been limited by low-frequency allogeneic cell engraftment. In this issue of Blood, Peranteau and colleagues have taken a highly significant stepforwardtowardrealizingenhanced IUHCT.

Following up on studies by others that demonstrated enhancement of homing and engraftment of long-term mouse marrow competitive repopulating HSCs in lethally irradiated congenic mice by inhibition/deletion of the dipeptidylpeptidase IV (DPPIV) activity of CD26,1 Peranteau et al convincingly demonstrated enhanced allogeneic donor cell homing and competitive engraftment of mouse HSCs in utero in mice. The beauty of both studies (Peranteau et al and Christopherson et al1), and of another study demonstrating that inhibition of CD26 improves engraftment of retrovirally transduced mouse bone marrow HSCs,2 is the simplicity of the procedure: pretreat donor cell populations of HSCs for 15 minutes with either Diprotin A (Ile-Pro-Ile, per Peranteau et al, Christopherson et al,1 and Tian et al2) or Val-Pyr1 and infuse.

The stromal cell–derived factor 1 (SDF-1)/CXCL12-CXCR4 axis has been implicated in homing, retention, and mobilization of HSCs.3 DPPIV activity of CD26 selectively tunicates and inactivates SDF-1/CXCL12 so it is no longer chemotactic but can block chemotaxis of full-length SDF-1/CXCL12.1,3 Inhibiting CD26 enhances potency of SDF-1/CXCL12 for attraction and retention of HSCs (Peranteau et al and Broxmeyer et al3). SDF-1/CXCL12 has other functions, including enhancement of HSC survival3 and replating (“self-renewal”) capacity of progenitors (H.E.B., unpublished data, December 2005). Inhibition of CD26 further enhances these activities. These effects may in part also be responsible after inhibition of CD26 for enhanced competitive engraftment of HSCs (Peranteau et al, Christopherson et al,1 and Tian et al2). Because Diprotin A and Val-Pyr inhibition of CD26 is time related and reversible, and not as potent as CD26 deletion,1 efforts to understand what modulates CD26 expression,4 prolonging CD26 inhibition (either by next-generation inhibitors or better use of inhibitors involving in vivo treatment of recipients, since CD26 is expressed on T cells and other cells),3 along with treatment of donor cells, may further enhance HSC homing and engraftment.

The intriguing observation that inhibition of CD26 enhanced engraftment in utero across full MHC barriers and also in an outbred strain of mice, as observed by Peranteau et al, suggests that CD26 inhibition may potentially enhance engraftment of HSCs from cord blood, bone marrow, and mobilized peripheral blood in an HLA-disparate allogeneic donor cell setting with concomitant decreased graft-versus-host disease. Such possibilities should be addressed in larger animal models (eg, monkeys, dogs) and in human clinical trials, studies that will require clinical-grade CD26 inhibitors.

Exact mechanisms of enhancement of HSC engraftment by CD26 inhibition will have to be better understood. Assays for homing of HSCs used by many investigators must be improved. Studies toward characterizing potential HSC niches are ongoing. However, efforts to truly understand the microenvironmental niche and its dynamics will require real-time sequential 3-dimensional imaging in vivo with resolution well beyond that currently available to detect movement of donor HSCs, contact with phenotypically and functionally defined subsets of stromal and endothelial cells, and reciprocal cell-cell and cytokine-cell interactions.

The author declares no competing financial interests.