A Human Hematopoietic Niche Model Supporting Hematopoietic Stem and Progenitor Cells In Vitro

Braham, Maaike V.J.; Yim, Amélie S P Li; Mateos, Jara Garcia; Minnema, Monique C.; Dhert, Wouter J.A.; Öner, F. Cumhur; Robin, Catherine; Alblas, Jacqueline

doi:10.1002/adhm.201801444

Cited by 35 publications

(31 citation statements)

References 52 publications

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“…Here, we show increasing local presence of HUVECs and MSCs dramatically increases the expansion of differentiated hematopoieitic cells but not at the expense of maintaining a subpopulation of HSCs. This general result is consistent with Braham et al, who demonstrated that co-culturing HSCs with mesenchymal stromal and endothelial progenitor cells in alginate or Matrigel promoted hematopoeitic proliferation; [36] however, our platform provides the first evidence that vascular density plays a dose-dependent role in modulating HSC behavior.…”

Section: Discussionsupporting

confidence: 92%

Hydrogels Containing Gradients in Vascular Density Reveal Dose-Dependent Role of Angiocrine Cues on Stem Cell Behavior

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Barnhouse

Gilchrist

et al. 2021

Preprint

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Biomaterials that replicate patterns of microenvironmental signals from the stem cell niche offer the potential to refine platforms to regulate stem cell behavior. While significant emphasis has been placed on understanding the effects of biophysical and biochemical cues on stem cell fate, vascular-derived or angiocrine cues offer an important alternative signaling axis for biomaterial-based stem cell platforms. Elucidating dose-dependent relationships between angiocrine cues and stem cell fate are largely intractable in animal models and two-dimensional cell culture. In this study, we leverage microfluidic mixing devices to generate three-dimensional hydrogels containing lateral gradients in vascular density alongside murine hematopoietic stem cells (HSCs). Regional differences in vascular density can be generated via embossed gradients in cell, matrix, or growth factor density. HSCs co-cultured alongside vascular gradients reveal spatial patterns of HSC phenotype in response to angiocrine signals. Notably, decreased Akt signaling in high vessel density regions led to increased expansion of lineage-positive hematopoietic cells. This approach offers a combinatorial tool to rapidly screen a continuum of microenvironments with varying vascular, biophysical, and biochemical cues to reveal the influence of local angiocrine signals on HSC fate.

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Section: Discussionsupporting

confidence: 92%

Hydrogels Containing Gradients in Vascular Density Reveal Dose-Dependent Role of Angiocrine Cues on Stem Cell Behavior

Ngo

Barnhouse

Gilchrist

et al. 2021

Preprint

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“…In attempt to add complexity to mimic the BM microenvironment, Braham et al (2019) used endothelial progenitor cells isolated from cord blood and allowed them to form a complex cellular environment together with MSC-derived adipocytes and osteoblasts. These culture conditions can be potentially used to maintain HSCs over long periods without the addition of any cytokines, as the mesenchymal and endothelial compartments should provide all the required cytokine and angiocrine factors.…”

Section: Generation Of Models For Experimental Approachesmentioning

confidence: 99%

Bioengineering the Bone Marrow Vascular Niche

Bessy

Itkin

Passaro

2021

Front. Cell Dev. Biol.

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The bone marrow (BM) tissue is the main physiological site for adult hematopoiesis. In recent years, the cellular and matrix components composing the BM have been defined with unprecedent resolution, both at the molecular and structural levels. With the expansion of this knowledge, the possibility of reproducing a BM-like structure, to ectopically support and study hematopoiesis, becomes a reality. A number of experimental systems have been implemented and have displayed the feasibility of bioengineering BM tissues, supported by cells of mesenchymal origin. Despite being known as an abundant component of the BM, the vasculature has been largely disregarded for its role in regulating tissue formation, organization and determination. Recent reports have highlighted the crucial role for vascular endothelial cells in shaping tissue development and supporting steady state, emergency and malignant hematopoiesis, both pre- and postnatally. Herein, we review the field of BM-tissue bioengineering with a particular focus on vascular system implementation and integration, starting from describing a variety of applicable in vitro models, ending up with in vivo preclinical models. Additionally, we highlight the challenges of the field and discuss the clinical perspectives in terms of adoptive transfer of vascularized BM-niche grafts in patients to support recovering hematopoiesis.

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“…60 Recently, Braham et al investigated multiple combinations of stromal cells in a hydrogel system, and found that optimal support of hematopoietic stem and progenitor cells (HSPCs) was provided by adipogenic and osteogenic cells, along with endothelial cells without the need for supplemental cytokine addition. 5…”

Section: Factors Poulos Et Al Demonstrated That Bone Marrow Endothementioning

confidence: 99%

Perivascular Secretome Influences Hematopoietic Stem Cell Maintenance in a Gelatin Hydrogel

Barnhouse

Petrikas

Crosby

et al. 2020

Preprint

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Adult hematopoietic stem cells (HSCs) produce the body's full complement of blood and immune cells. They reside in specialized microenvironments, or niches, within the bone marrow. The perivascular niche near blood vessels is believed to help maintain primitive HSCs in an undifferentiated state but demonstration of this effect is difficult. In vivo studies make it challenging to determine the direct effect of the endosteal and perivascular niches as they can be in close proximity, and two-dimensional in vitro cultures often lack an instructive extracellular matrix environment. We describe a tissue engineering approach to develop and characterize a three-dimensional perivascular tissue model to investigate the influence of the perivascular secretome on HSC behavior. We generate 3D endothelial networks in methacrylamide-functionalized gelatin hydrogels using human umbilical vein endothelial cells (HUVECs) and mesenchymal stromal cells (MSCs). We identify a subset of secreted factors important for HSC function, and examine the response of primary murine HSCs in hydrogels to the perivascular secretome. Within 4 days of culture, perivascular conditioned media promoted maintenance of a greater fraction of hematopoietic stem and progenitor cells. This work represents an important first-generation perivascular model to investigate the role of niche secreted factors on the maintenance of primary HSCs.

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A Human Hematopoietic Niche Model Supporting Hematopoietic Stem and Progenitor Cells In Vitro

Cited by 35 publications

References 52 publications

Hydrogels Containing Gradients in Vascular Density Reveal Dose-Dependent Role of Angiocrine Cues on Stem Cell Behavior

Hydrogels Containing Gradients in Vascular Density Reveal Dose-Dependent Role of Angiocrine Cues on Stem Cell Behavior

Bioengineering the Bone Marrow Vascular Niche

Perivascular Secretome Influences Hematopoietic Stem Cell Maintenance in a Gelatin Hydrogel

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