Bone marrow cell trafficking following intravenous administration

Abstract

To address trafficking of transplanted marrow cells immediately after intravenous infusion, we examined the early fate of infused non‐adherent, low‐density donor bone marrow cells in a syngeneic mouse model. The presence of infused donor cells, marked with indium‐111 oxine (111In), with the fluorescent dye PKH26, or by a detectable transgene marker, was evaluated at 3–48 h in a variety of tissues, including peripheral blood. All three cell‐marking methods indicated a rapid (< 4 h) influx of cells into the bone marrow, liver, spleen, muscle and other tissues. Moreover, these tissues remained positive for the 48 h observation period. Interestingly, analysis of PKH26‐positive cells in non‐myeloablated animals demonstrated that approximately 17% of infused donor marrow cells localized to the marrow space within 15 h, whereas a smaller proportion of donor cells (~ 1–2%) localized to the marrow in recipients preconditioned by irradiation. In an effort to enrich for cells that specifically home to the bone marrow, PKH26‐labelled donor marrow cells were recovered from the first host and infused into a secondary recipient. Although this was a phenotypically undefined population of cells, no increase was observed in the relative fraction of PKH26‐labelled cells returning or ‘homing’ to the marrow of the second recipient. Taken together, these data suggest both that marrow engraftment may be mediated by non‐specific ‘seeding’ rather than a specific homing signal, and that efficient targeting of transplanted cells to the marrow is a complex multifaceted process.

Transplanted Hematopoietic Cells Seed in Clusters in Recipient Bone Marrow In Vivo

“…The decrease in number of bright cells and the increase in heterogeneity of fluorescence intensity most likely reflect the proliferative activity of some HSPCs during transition to secondary clusters. PKH membrane linkers are equally distributed among daughter cells during division, resulting in dilution of the dye below the detection threshold of optical imaging [9,11,13,14]. Some hematopoietic progenitors have been shown to divide early after transplantation [9][10][11][12].…”

“…First, we wanted to determine whether the clusters reflect a real aggregation tendency of transplanted cells, because some progenitors can divide very early after transplantation [9][10][11][12]. Therefore, we used PKH membrane linkers, which are evenly distributed among daughter cells and are diluted during division [9,11,13,14]. Second, we assessed whether cells of various antigenic types are incorporated in common clusters or whether aggregation of the cells is antigen specific.…”

Homing, cell cycle kinetics and fate of transplanted hematopoietic stem cells

“…26 As a result, distribution of infused cells shortly after transplantation results in non-specific seeding of cells in various tissues rather than a specific and directed trafficking of cells to hematopoietic sites. 27 In fact, several earlier studies [28][29][30] noted the generalized distribution of transplanted cells in different organs of the recipient, challenging therefore the notion of definitive migration of transplanted cells to hematopoietic tissues. When the pattern of migration of prenatally transplanted hematopoietic cells was examined in a murine in utero transplantation model, Shaaban et al 31 also concluded that homing to the fetal liver is non-selective.…”

“…26,27 These studies maintain that homing is a non-specific process resulting in the distribution of transplanted HSC in the host on the basis of organ mass and the complexity of the capillary bed of each organ. 26 As a result, distribution of infused cells shortly after transplantation results in non-specific seeding of cells in various tissues rather than a specific and directed trafficking of cells to hematopoietic sites.…”

Device and application development for haematopoietic stem and progenitor cell (HSPC) and mesenchymal stromal cell (MSC) 3D spheroid cultures

“…Reduced engraftment may also be hampered by BM stromal damage as a result of myeloablative regimens, which compromise the BM microenvironment [224,225]. MSC co--administration has been suggested as a strategy to improve the low engraftment efficiency of CB by facilitating BM repair and maintaining HSPC.…”