Emerging Strategies to Enhance Homing and Engraftment of Hematopoietic Stem Cells

Abstract

Successful clinical outcomes from transplantation of hematopoietic stem cells (HSCs) depend upon efficient HSC homing to bone marrow (BM), subsequent engraftment, and, finally, BM repopulation. Homing of intravenously administered HSCs from peripheral blood (PB) through the circulation to the BM stem cell niches, which is the first critical step that precedes their engraftment, is enforced by chemotactic factors released in the BM microenvironment that chemoattract HSCs. These chemotactic factors include α-chemokine stromal-derived factor 1 (SDF-1), the bioactive phosphosphingolipids sphingosine-1-phosphate (S1P) and ceramid-1-phosphate (C1P), and the extracellular nucleotides ATP and UTP. Stem cells may also respond to a Ca2+ or H+ gradient by employing calcium- or proton-sensing receptors, respectively. In this review, we will present emerging strategies based on ex vivo manipulation of graft HSCs that are aimed at enhancing the responsiveness of HSCs to BM-secreted chemoattractants and/or promoting HSC adhesion and seeding efficiency in the BM microenvironment.

Early assessment of dosimetric and biological differences of total marrow irradiation versus total body irradiation in rodents

“…With respect to TMI, the chemokine gradient may be reversed (higher SDF-1 in BM regions relative to non skeletal organs), enabling directional migration of cells towards the BM niche at relatively higher numbers. Our results are consistent with a role for SDF-1α/CXCR4 interactions in hematopoietic stem cell (HSC) homing to bone marrow [9, 16–18]. …”

“…Then, we developed a clinically relevant TMI and chemotherapy transplant model to test the hypothesis that TMI would result in efficient engraftment while reducing risks of conditioning- and acute graft-versus-host disease-(GVHD)-mediated tissue damage. Furthermore, we analyzed underlying molecular mechanisms of those benefits of TMI by measuring the changes in stromal-derived factor 1 (SDF-1), a chemoattractant associated with successful engraftment [9], as well as epidermal growth factor (EGF) and amphiregulin (AREG), which are growth factors associated with wound healing responses.…”

Not All Stem Cells Are Equally Great: Donor Single-Nucleotide Polymorphisms (SNP) May Matter More Than Previously Thought

“…HSCT could be either allogeneic or autologous. 25,26 Cryopreservation techniques now allow autologous bone marrow to be stored safely and indefinitely without catastrophic loss of stem cells on thawing. Umbilical cord blood from neonates contains substantial numbers of haematopoietic stem cells, which can be harvested at delivery, frozen, and then transplanted to patients after cell counts and virological screening are performed.…”

Enhancing human cord blood hematopoietic stem cell engraftment by targeting nuclear hormone receptors

“…Human HSC are major contributors for HCT [5,6]. Once infused into peripheral blood of recipients, HSC and HPC migrate and engraft in bone marrow (BM) niches, where a new hematopoietic system builds up [7,8]. Three major sources of HSC for HCT are: BM, peripheral blood and CB [9,10].…”

“…However, delayed hematopoietic recovery and immune reconstitution due to limited numbers of HSCs are major limiting factors preventing the wider use of HCT based cell therapy. Progress to improve CB HSC engraftment and reconstitution includes mitigating effects of Extra Physiologic Oxygen Shock/Stress (EPHOSS) during cell collection [14], ex vivo expansion of HSC [15–17*] and enhancing HSC homing efficiency [18]. …”