The Homing of Hematopoietic Stem Cells to the Bone Marrow

Hardy, Cheryl L.

doi:10.1097/00000441-199530950-00005

Cited by 51 publications

(30 citation statements)

References 39 publications

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“…We speculate that the cytokines could be inducing adhesion molecules on the SRC enabling efficient homing to the murine microenvironment. 19 Future studies should include detailed kinetic experiments where cytokines are given for different times and doses starting from before the transplant. Similarly the AC could be acting to prevent nonspecific homing.…”

Section: Discussionmentioning

confidence: 99%

Cytokine treatment or accessory cells are required to initiate engraftment of purified primitive human hematopoietic cells transplanted at limiting doses into NOD/SCID mice

Bonnet

Bhatia

Wang

et al. 1999

Bone Marrow Transplant

120

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Summary:Little is known about the cell types or mechanisms that underlie the engraftment process. Here, we have examined parameters affecting the engraftment of purified human Lin ؊ CD34 ؉ CD38 ؊ normal and AML cells transplanted at limiting doses into NOD/SCID recipients. Mice transplanted with 500 to 1000 Lin ؊ CD34 ؉ CD38 Ϫ cord blood (CB) or AML cells required the co-transplantation of accessory cells (ACs) or short-term in vivo cytokine treatment for engraftment, whereas transplantation of higher doses (Ͼ5000 Lin ؊ CD34 ؉ CD38 ؊ cells) did not show these requirements suggesting that ACs are effective for both normal and leukemic stem cell engraftment in this model. Mature Lin ؉ CD34 ؊ and primitive Lin ؊ CD34 ؉ CD38 ؉ cells were capable of acting as ACs even though no repopulating cells are present. Cytokine treatment of NOD/SCID mice could partially replace the requirement for co-transplantation of AC. Furthermore, no difference was seen between the percentage of engrafted mice treated with cytokines for only the first 10 days after transplant compared to those receiving cytokines for the entire time of repopulation. Surprisingly, no engraftment was detected in mice when cytokine treatment was delayed until 10 days posttransplant. Together, these studies suggest that the engraftment process requires pluripotent stem cells plus accessory cells or cytokine treatment which act early after transplantation. The NOD/SCID xenotransplant system provides the means to further clarify the processes underlying human stem cell engraftment.

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Section: Discussionmentioning

confidence: 99%

Cytokine treatment or accessory cells are required to initiate engraftment of purified primitive human hematopoietic cells transplanted at limiting doses into NOD/SCID mice

Bonnet

Bhatia

Wang

et al. 1999

Bone Marrow Transplant

120

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“…Homing has been studied extensively both in vivo and in vitro and is believed to rely on adhesion molecule interactions between stromata, which consist of stromal cells and extracellular matrix, and stem cells. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] In vivo homing studies typically rely on infusion of a labeled or detectable HSC population and subsequent detection at various times after the transplantation. 16,19 In this approach, the recipients must be examined early enough (approximately 24 hours or earlier) that only infused cells, and not their progeny, are detected.…”

Section: Introductionmentioning

confidence: 99%

An in vitro model of hematopoietic stem cell homing demonstrates rapid homing and maintenance of engraftable stem cells

Frimberger

Stering

Quesenberry

2001

Blood

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Hematopoietic stem cell (HSC) homing is believed to rely heavily on adhesion interactions between stem cells and stroma. An in vitro assay was developed for adhesion of engraftable HSCs in bone marrow suspensions to pre-established Dextertype long-term bone marrow culture stromal layers. The cell numbers in the adherent layer and supernatant were examined, along with the engraftment capability of adherent layer cells to indicate the number of HSCs that homed to in vitro stroma. The cell number in the supernatant declined over the 24-hour period. The number of test cells adhering to the stromal layer increased during the first hour and then fell at 6 and 24 hours. The number of test HSCs adhering to the stromal layer was substantial at 20 minutes, increased during the first hour, and then remained constant at 1, 6, and 24 hours of adhesion. These data indicate that adhesion of engraftable HSCs occurs quickly and increases during the first hour of contact with pre-established stroma, that adhesion plateaus within 1 hour of contact, and that HSCs maintain their engraftment capability for at least 24 hours of stromal adhesion. Long-term engraftment from test cells at more than 1 hour of adhesion represents 70.7% of the predicted engraftment from equivalent numbers of unmanipulated marrow cells, indicating that 2 of 3 test engraftable HSCs adhered. These findings demonstrate the usefulness of this model system for studying stemstromal adhesion, allowing further dissection of the mechanism of HSC homing and exploration of possible manipulations of the process. IntroductionHematopoietic stem cell (HSC) homing is the process by which HSCs, infused intravenously in the transplantation setting, specifically extravasate in the bone marrow to engraft and proliferate there. Homing has been studied extensively both in vivo and in vitro and is believed to rely on adhesion molecule interactions between stromata, which consist of stromal cells and extracellular matrix, and stem cells. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] In vivo homing studies typically rely on infusion of a labeled or detectable HSC population and subsequent detection at various times after the transplantation. 16,19 In this approach, the recipients must be examined early enough (approximately 24 hours or earlier) that only infused cells, and not their progeny, are detected. However, testing this early can make it difficult to ascertain that the cells are truly homed and not migratory. Also, to dissect the mechanisms of homing, it would be desirable to conduct various manipulations, such as adding an adhesion receptor blocking antibody, and this can be cumbersome or even impossible in vivo. On the other hand, in vitro systems are relatively easy to manipulate, but the assay result can be difficult to interpret. Most in vitro homing studies examine adhesion of a hematopoietic cell population or cell line to a test substrate, such as purified extracellular matrix molecule coatings or stromal cell lines, under various conditions. 20-29 ...

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“…We used our CD34 ϩ cell concentrations over time as a pharmacokinetic curve. Our study is based on the assumption of a bi-compartmental model, 25 the first being the PB and the second the bone marrow microenvironment. The highest concentration of CD34 ϩ cells in PB was observed just after infusion.…”

Section: Discussionmentioning

confidence: 99%

Clearance kinetics of CD34+ cells from peripheral blood: an independent predictor of hematologic recovery after high-dose chemotherapy and hematopoietic stem cell transplantation

Dhondt

Wuu

André

et al. 1999

Bone Marrow Transplant

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Summary:We measured the concentration of CD34 ؉ cells in peripheral blood (PB) . h prior to and ., 1, 3, 6, and 12 h following hematopoietic stem cell (HSC) infusion in 34 breast cancer patients treated with high-dose chemotherapy (HDC). The decrease in these concentrations over time enabled us to determine the clearance kinetics of CD34 ؉ cells from PB. The absolute number of CD34 ؉ cells in PB generally peaked at . h after infusion, then rapidly declined from 1 to 3 h post infusion and continued to fall until 12 h post transplant, but more slowly. In univariate analysis, CD34 ؉ cells/kg infused, CFU-GM/kg infused, the CD34 ؉ count at . h, and the 12-h clearance of CD34 ؉ cells from PB were predictors of hematologic recovery, as were each of the two phases of clearance when the slope was divided into rapid and slow phases (from . to 3 and from 3 to 12 h post transplant, respectively). We then stratified our population by the number of CD34 ؉ cells/kg infused. In group 1, patients received р7.5 × 10 6 CD34 ؉ cells/kg; in group 2, Ͼ7.5 × 10 6 CD34 ؉ cells/kg. After adjusting for CD34 ؉ cells injected, age, and purged or unpurged graft in multivariate analysis, the 12 h clearance remained a predictor of hematologic recovery in group 1. In addition, the second phase of clearance (from 3 to 12 h after infusion) was an even better predictor than the 12 h clearance. In group 2, however, no statistically significant correlation was observed, even with the number of HSC injected. Results suggest that rapidity of clearance of CD34 ؉ cells from PB is an independent indicator of hematologic recovery in patients receiving lower doses of CD34 ؉ cells. When the cell dose injected is over a threshold, PB clearance correlations with hematologic recovery are masked.

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The Homing of Hematopoietic Stem Cells to the Bone Marrow

Cited by 51 publications

References 39 publications

Cytokine treatment or accessory cells are required to initiate engraftment of purified primitive human hematopoietic cells transplanted at limiting doses into NOD/SCID mice

Cytokine treatment or accessory cells are required to initiate engraftment of purified primitive human hematopoietic cells transplanted at limiting doses into NOD/SCID mice

An in vitro model of hematopoietic stem cell homing demonstrates rapid homing and maintenance of engraftable stem cells

Clearance kinetics of CD34+ cells from peripheral blood: an independent predictor of hematologic recovery after high-dose chemotherapy and hematopoietic stem cell transplantation

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