Regeneration of Bone Marrow from Adipose-Derived Stromal Cells - a Novel Approach for the Treatment of Fibroblastic Bone Marrow Diseases.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2343-2343
Author(s):  
Rei Ogawa ◽  
Hiroshi Mizuno ◽  
Hiko Hyakusoku ◽  
Makoto Migita ◽  
Takashi Shimada
Keyword(s):  
Bone Marrow ◽  
Stromal Cells ◽  
Fluorescent Protein ◽  
Hematopoietic Cells ◽  
Immunohistochemical Analysis ◽  
Hematopoietic Stem ◽  
Adipose Derived Stromal Cells ◽  
Bone Marrow Regeneration

Abstract BACKGROUND: Taking advantage of homogeneously marked cells from green fluorescent protein (GFP) transgenic mice, we have previously demonstrated that adipose-derived stromal cells (ASCs) and bone marrow-derived stromal cells (BSCs) differentiate into a variety of cell lineages both in vitro and in vivo. In the present study, we extended this approach to regenerate bone marrow. METHODS: ASCs isolated from the inguinal fat pads of GFP mice were cultured in vitro for five passages and seeded onto hydroxyapatites with small pores. The hydroxyapatites including ASCs were subsequently implanted into immunocompetent mice subcutaneously. Two months later, the hydroxyapatites were extirpated for histological and immunohistochemical analyses. RESULTS: The specimens were covered with adipose tissues including extensively developed microvessels and GFP+ cells. Histological examination showed that the pores were filled with typical bone marrow composed of adipocytes, hematopoietic cells, vasculatures, and matrix. Immunohistochemical analysis confirmed that the GFP+ ASCs had differentiated into osteoblasts and vascular endothelial cells, but not hematopoietic cells. CONCLUSION: We demonstrated for the first time that bone marrow can be regenerated from ASCs. Bone marrow regeneration from non-bone-marrow-derived cells will have a great impact on the treatment of various bone marrow-related disorders, in particular idiopathic myelofibrosis and osteopetrosis, in which there is no place for hematopoietic stem cells to survive. Furthermore, in combination with gene transfer, bone marrow regeneration may be applied to the development of novel therapeutic approaches for various kinds of hematopoietic diseases.

In Vivo Generation of Engraftable Murine Hematopoietic Stem Cells from Induced Pluripotent Stem Cells through Hemogenic Endothelium

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3866-3866
Author(s):  
Masao Tsukada ◽  
Satoshi Yamazaki ◽  
Yasunori Ota ◽  
Hiromitsu Nakauchi
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Stromal Cells ◽  
Pluripotent Stem Cells ◽  
Hematopoietic Cells ◽  
Hematopoietic Stem ◽  
Teratoma Formation

Abstract Introduction Generation of engraftable hematopoietic stem cells (HSCs) from pluripotent stem cells (PSCs) has long been thought an ultimate goal in the field of hematology. Numerous in vitro differentiation protocols, including trans-differentiation and forward programming approaches, have been reported but have so far failed to generate fully functional HSCs. We have previously demonstrated proof-of-concept for the in vivo generation of fully functional HSCs from induced PSCs (iPSCs) through teratoma formation (Suzuki et al., 2013). However, this method is time-consuming (taking over two months), HSCs are generated at low frequencies, and additionally require co-injection on OP9 stromal cells and SCF/TPO cytokines. Here, we present optimization of in vivo HSC generation via teratoma formation for faster, higher-efficiency HSC generation and without co-injection of stromal cells or cytokines. Results First, we screened reported in vitro trans-differentiation and forward programming strategies for their ability to generate HSCs in vivo within the teratoma assay. We tested iPSCs transduced with the following dox-inducible TF overexpression vectors: (1) Gfi1b, cFOS and Gata2 (GFG), which induce hemogenic endothelial-like cells from fibroblast (Pereira et al.,2013); (2) Erg, HoxA9 and Rora (EAR), which induce short-term hematopoietic stem/progenitor cell (HSPC) formation during embryoid body differentiation (Doulatov et,al., 2013); and (3) Foxc1, which is highly expressed the CAR cells, a critical cell type for HSC maintenance (Oomatsu et al.,2014). We injected iPSCs into recipient mice, without co-injection of stromal cells or cytokines, and induced TF expression after teratoma formation by dox administration. After four weeks, GFG-derived teratomas contained large numbers of endothelial-like and epithelial-like cells, and importantly GFG-derived hematopoietic cells could also be detected. EAR-teratomas also generated hematopoietic cells, although at lower frequencies. By contrast, hematopoietic cells were not detected in control teratomas or Foxc1-teratomas. Through use of iPSCs generated from Runx1-EGFP mice (Ng et al. 2010), and CUBIC 3D imaging technology (Susaki et al. 2014), we were further able to demonstrate that GFG-derived hematopoietic cells were generated through a haemogenic endothelium precursor. Next, we assessed whether HSPC-deficient recipient mice would allow greater expansion of teratoma-derived HSCs. This was achieved by inducing c-kit deletion within the hematopoietic compartment of recipient mice (Kimura et al., 2011) and resulted in a ten-fold increase in the peripheral blood frequency of iPSC-derived hematopoietic cells. We further confirmed similar increases in iPSC-derived bone marrow cells, and in vivo HSC expansion, through bone marrow transplantation assays. Finally, we have been able to shorten the HSC generation time in this assay by five weeks through use of transplantable teratomas, rather than iPSCs. Conclusions We have demonstrated that GFG-iPSCs induce HSC generation within teratomas, via a hemogenic endothelium precursor, and that use of HSPC-deficient recipient mice further promotes expansion of teratoma-derived HSCs. These modifications now allow us to generate engraftable HSCs without co-injection of stromal cells or cytokines. Additionally, use of transplantable teratomas reduced HSC generation times as compared with the conventional assay. These findings suggest that our in vivo system provides a promising strategy to generate engraftable HSCs from iPSCs. Disclosures No relevant conflicts of interest to declare.

scholarly journals Primitive Human Hematopoietic Cells Are Enriched in Cord Blood Compared With Adult Bone Marrow or Mobilized Peripheral Blood as Measured by the Quantitative In Vivo SCID-Repopulating Cell Assay

Blood ◽  
1997 ◽  
Vol 89 (11) ◽  
pp. 3919-3924 ◽  
Author(s):  
Jean C.Y. Wang ◽  
Monica Doedens ◽  
John E. Dick
Keyword(s):  
Bone Marrow ◽  
Cord Blood ◽  
Peripheral Blood ◽  
Hematopoietic Cells ◽  
Allogeneic Transplantation ◽  
Functional Assay ◽  
Hematopoietic Stem ◽  
Mobilized Peripheral Blood

Abstract We have previously reported the development of in vivo functional assays for primitive human hematopoietic cells based on their ability to repopulate the bone marrow (BM) of severe combined immunodeficient (SCID) and nonobese diabetic/SCID (NOD/SCID) mice following intravenous transplantation. Accumulated data from gene marking and cell purification experiments indicate that the engrafting cells (defined as SCID-repopulating cells or SRC) are biologically distinct from and more primitive than most cells that can be assayed in vitro. Here we demonstrate through limiting dilution analysis that the NOD/SCID xenotransplant model provides a quantitative assay for SRC. Using this assay, the frequency of SRC in cord blood (CB) was found to be 1 in 9.3 × 105 cells. This was significantly higher than the frequency of 1 SRC in 3.0 × 106 adult BM cells or 1 in 6.0 × 106 mobilized peripheral blood (PB) cells from normal donors. Mice transplanted with limiting numbers of SRC were engrafted with both lymphoid and multilineage myeloid human cells. This functional assay is currently the only available method for quantitative analysis of human hematopoietic cells with repopulating capacity. Both CB and mobilized PB are increasingly being used as alternative sources of hematopoietic stem cells in allogeneic transplantation. Thus, the findings reported here will have important clinical as well as biologic implications.

Atelocollagen Sponge as a Stem Cell Implantation Scaffold for the Treatment of Scarred Vocal Folds

2010 ◽  
Vol 119 (11) ◽  
pp. 805-810 ◽  
Author(s):  
Satoshi Ohno ◽  
Shigeru Hirano ◽  
Ichiro Tateya ◽  
Shin-Ichi Kanemaru ◽  
Hiroo Umeda ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Stromal Cells ◽  
Fluorescent Protein ◽  
In Vitro Study ◽  
Vocal Folds ◽  
Green Fluorescent ◽  
Cell Implantation

Objectives: Treatment of vocal fold scarring remains a therapeutic challenge. Our group previously reported the efficacy of treating injured vocal folds by implantation of bone marrow—derived stromal cells containing mesenchymal stem cells. Appropriate scaffolding is necessary for the stem cell implant to achieve optimal results. Terudermis is an atelocollagen sponge derived from calf dermis. It has large pores that permit cellular entry and is degraded in vivo. These characteristics suggest that this material may be a good candidate for use as scaffolding for implantation of cells. The present in vitro study investigated the feasibility of using Terudermis as such a scaffold. Methods: Bone marrow—derived stromal cells were obtained from GFP (green fluorescent protein) mouse femurs. The cells were seeded into Terudermis and incubated for 5 days. Their survival, proliferation, and expression of extracellular matrix were examined. Results: Bone marrow—derived stromal cells adhered to Terudermis and underwent significant proliferation. Immunohistochemical examination demonstrated that adherent cells were positive for expression of vimentin, desmin, fibronectin, and fsp1 and negative for beta III tubulin. These findings indicate that these cells were mesodermal cells and attached to the atelocollagen fibers biologically. Conclusions: The data suggest that Terudermis may have potential as stem cell implantation scaffolding for the treatment of scarred vocal folds.

Hematopoiesis in Bone Marrow Regenerated from Adipose-Derived Stromal Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4108-4108
Author(s):  
Makoto Migita ◽  
Atsushi Fujita ◽  
Rei Ogawa ◽  
Takahiro Ueda ◽  
Yoshitaka Fukunaga ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stromal Cells ◽  
Lentiviral Vector ◽  
Whole Body ◽  
Hematopoietic Stem ◽  
Adipose Derived Stromal Cells ◽  
In Vivo Bioluminescence Imaging ◽  
Lethal Irradiation ◽  
Hematoxylin Eosin

Abstract Background: Adipose-derived stromal cells (ASCs) are highly promising cells for tissue engineering because of their pluripotency and low donor morbidity. We have previously shown that ASCs differentiate into a variety of mesenchymal tissues including bone and bone marrow (BM) like architecture. Osteoblastic cells lining the endosteal surface are a key component of the hematopoietic niche to promote and regulate hematopoietic stem cells (HSCs). In the present study, we investigated whether ASCs derived BM can functionally support hematopoiesis. Methods: ASCs were isolated from the inguinal fat pads from C57/BL6 mice (Ly5.2) after collagenase treatment and were cultured for three passages in the culture plates. The attached cells were trypsinized and replated onto a hydoxyapatite (HA) scaffold with numerous small pores for 3 days. The scaffold with attached cells was implanted subcutaneously onto the back of C57/BL6 recipient mice. 4.0×105 Lineage negative (Lin-) Ly5.1 BM cells transduced with a lentiviral vector containing the luciferase (Luc) gene were intravenously administered into the recipient mice after lethal irradiation. After 8 weeks, the scaffolds including Luc+ cells were removed and re-transplanted to the lethally irradiated second recipient mice. Results: Excised HA scaffolds were totally covered with adipose tissues. Hematoxylin-eosin staining showed that microspores were filled with typical bone marrow architecture composed of adipocytes, vasculatures, stroma, and a variety of hematopoietic cells. In vivo bioluminescence imaging showed that Luc+ hematopoitic cells were detected in the scaffolds in the secondary transplanted mice for at least 6 months after transplantation. Bioluminescence signals were also detectable on the whole body including the head, extremities, chest, and abdomen after G-CSF injection. Conclusions: We demonstrated that BM could be regenerated by ASCs. The ASCs derived BM were capable of maintenance of hematopoietic progenitor cells in vivo. BM regeneration from non-BM cells raises new possibilities to treat various hematopoietic diseases.

Mesenchymal Stem and Progenitor Cells In the Mouse Bone Marrow Lack Expression of CD44.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2581-2581
Author(s):  
Hong Qian ◽  
Mikael Sigvardsson
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Stromal Cells ◽  
Stromal Cell ◽  
Hematopoietic Cells ◽  
Hematopoietic Stem ◽  
Colony Forming Unit ◽  
Stem And Progenitor Cells ◽  
Cell Fractions

Abstract Abstract 2581 The bone marrow (BM) microenvironment consists of a heterogeneous population including mesenchymal stem cells and as well as more differentiated cells like osteoblast and adipocytes. These cells are believed to be crucial regulators of hematopoetic cell development, however, so far, their identity and specific functions has not been well defined. We have by using Ebf2 reporter transgenic Tg(Ebf2-Gfp) mice found that CD45−TER119−EBF2+ cells are selectively expressed in non-hematopoietic cells in mouse BM and highly enriched with MSCs whereas the EBF2− stromal cells are very heterogenous (Qian, et al., manuscript, 2010). In the present study, we have subfractionated the EBF2− stromal cells by fluorescent activated cell sorter (FACS) using CD44. On contrary to previous findings on cultured MSCs, we found that the freshly isolated CD45−TER119−EBF2+ MSCs were absent for CD44 whereas around 40% of the CD45−TER119−EBF2− cells express CD44. Colony forming unit-fibroblast (CFU-F) assay revealed that among the CD45−LIN−EBF2− cells, CD44− cells contained generated 20-fold more CFU-Fs (1/140) than the CD44+ cells. The EBF2−CD44− cells could be grown sustainably in vitro while the CD44+ cells could not, suggesting that Cd44− cells represents a more primitive cell population. In agreement with this, global gene expression analysis revealed that the CD44− cells, but not in the CD44+ cells expressed a set of genes including connective tissue growth factor (Ctgf), collagen type I (Col1a1), NOV and Runx2 and Necdin(Ndn) known to mark MSCs (Djouad et al., 2007) (Tanabe et al., 2008). Furthermore, microarray data and Q-PCR analysis from two independent experiments revealed a dramatic downregulation of cell cycle genes including Cdc6, Cdca7,-8 and Ki67, Cdk4-6) and up-regulation of Cdkis such as p57 and p21 in the EBF2−CD44− cells, compared to the CD44+ cells indicating a relatively quiescent state of the CD44− cells ex vivo. This was confirmed by FACS analysis of KI67 staining. Furthermore, our microarray analysis suggested high expression of a set of hematopoietic growth factors and cytokines genes including Angiopoietin like 1, Kit ligand, Cxcl12 and Jag-1 in the EBF2−CD44− stromal cells in comparison with that in the EBF2+ or EBF2−CD44+ cell fractions, indicating a potential role of the EBF2− cells in hematopoiesis. The hematopoiesis supporting activity of the different stromal cell fractions were tested by in vitro hematopoietic stem and progenitor assays- cobblestone area forming cells (CAFC) and colony forming unit in culture (CFU-C). We found an increased numbers of CAFCs and CFU-Cs from hematopoietic stem and progenitor cells (Lineage−SCA1+KIT+) in culture with feeder layer of the EBF2−CD44− cells, compared to that in culture with previously defined EBF2+ MSCs (Qian, et al., manuscript, 2010), confirming a high capacity of the EBF2−CD44− cells to support hematopoietic stem and progenitor cell activities. Since the EBF2+ cells display a much higher CFU-F cloning frequency (1/6) than the CD44−EBF2− cells, this would also indicate that MSCs might not be the most critical regulators of HSC activity. Taken together, we have identified three functionally and molecularly distinct cell populations by using CD44 and transgenic EBF2 expression and provided clear evidence of that primary mesenchymal stem and progenitor cells reside in the CD44− cell fraction in mouse BM. The findings provide new evidence for biological and molecular features of primary stromal cell subsets and important basis for future identification of stage-specific cellular and molecular interaction pathways between hematopoietic cells and their cellular niche components. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Identification of a Hematopoietic Cell Population Emerging From Mouse Bone Marrow With Proliferative Potential In Vitro and Immunomodulatory Capacity

2021 ◽  
Vol 12 ◽  
Author(s):  
Catalina-Iolanda Marinescu ◽  
Mihai Bogdan Preda ◽  
Carmen Alexandra Neculachi ◽  
Evelyn Gabriela Rusu ◽  
Sinziana Popescu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stromal Cells ◽  
Hematopoietic Cells ◽  
Tumor Rejection ◽  
Proliferative Potential ◽  
Mouse Bone Marrow ◽  
Positive Outcomes ◽  
Immunomodulatory Properties

There is continuing interest in therapeutic applications of bone marrow-derived mesenchymal stromal cells (MSC). Unlike human counterparts, mouse MSC are difficult to propagate in vitro due to their contamination with adherent hematopoietic cells that overgrow the cultures. Here we investigated the properties of these contaminating cells, referred to as bone marrow-derived proliferating hematopoietic cells (BM-PHC). The results showed that both BM-PHC and MSC had strong immunomodulatory properties on T cells in vitro, with PGE2 and NO involved in this mechanism. However, BM-PHC were stronger immunomodulators than MSC, with CCL-6 identified as putative molecule responsible for superior effects. In vivo studies showed that, in contrast to BM-PHC, MSC endorsed a more rapid xenograft tumor rejection, thus indicating a particular context in which only MSC therapy would produce positive outcomes. In conclusion, bone marrow contains two cell populations with immunomodulatory properties, which are valuable sources for therapeutic studies in specific disease-relevant contexts.

scholarly journals Native associations of early hematopoietic stem cells and stromal cells isolated in bone marrow cell aggregates

Blood ◽  
1994 ◽  
Vol 83 (2) ◽  
pp. 361-369 ◽  
Author(s):  
PE Funk ◽  
PW Kincade ◽  
PL Witte
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Stromal Cells ◽  
Stromal Cell ◽  
Hematopoietic Cells ◽  
Hematopoietic Stem ◽  
Factor C

In suspensions of murine bone marrow, many stromal cells are tightly entwined with hematopoietic cells. These cellular aggregations appear to exist normally within the marrow. Previous studies showed that lymphocytes and stem cells adhered to stromal cells via vascular cell adhesion molecule 1 (VCAM1). Injection of anti-VCAM1 antibody into mice disrupts the aggregates, showing the importance of VCAM1 in the adhesion between stromal cells and hematopoietic cells in vivo. Early hematopoietic stem cells were shown to be enriched in aggregates by using a limiting-dilution culture assay. Myeloid progenitors responsive to WEHI-3CM in combination with stem cell factor (c-kit ligand) and B220- B-cell progenitors responsive to insulin-like growth factor-1 in combination with interleukin-7 are not enriched. We propose a scheme of stromal cell-hematopoietic cell interactions based on the cell types selectively retained within the aggregates. The existence of these aggregates as native elements of bone marrow organization presents a novel means to study in vivo stem cell-stromal cell interaction.

scholarly journals Native associations of early hematopoietic stem cells and stromal cells isolated in bone marrow cell aggregates

Blood ◽  
1994 ◽  
Vol 83 (2) ◽  
pp. 361-369 ◽  
Author(s):  
PE Funk ◽  
PW Kincade ◽  
PL Witte
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Stromal Cells ◽  
Stromal Cell ◽  
Hematopoietic Cells ◽  
Hematopoietic Stem ◽  
Factor C

Abstract In suspensions of murine bone marrow, many stromal cells are tightly entwined with hematopoietic cells. These cellular aggregations appear to exist normally within the marrow. Previous studies showed that lymphocytes and stem cells adhered to stromal cells via vascular cell adhesion molecule 1 (VCAM1). Injection of anti-VCAM1 antibody into mice disrupts the aggregates, showing the importance of VCAM1 in the adhesion between stromal cells and hematopoietic cells in vivo. Early hematopoietic stem cells were shown to be enriched in aggregates by using a limiting-dilution culture assay. Myeloid progenitors responsive to WEHI-3CM in combination with stem cell factor (c-kit ligand) and B220- B-cell progenitors responsive to insulin-like growth factor-1 in combination with interleukin-7 are not enriched. We propose a scheme of stromal cell-hematopoietic cell interactions based on the cell types selectively retained within the aggregates. The existence of these aggregates as native elements of bone marrow organization presents a novel means to study in vivo stem cell-stromal cell interaction.

scholarly journals Bone Marrow Stromal Cells: Characterization and Clinical Application

1999 ◽  
Vol 10 (2) ◽  
pp. 165-181 ◽  
Author(s):  
P.H. Krebsbach ◽  
S.A. Kuznetsov ◽  
P. Bianco ◽  
P. Gehron Robey
Keyword(s):  
Bone Marrow ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Hematopoietic Cells ◽  
Marrow Stromal Cells ◽  
Proliferative Potential ◽  
Bone Marrow Stroma ◽  
Marrow Stroma

The bone marrow stroma consists of a heterogeneous population of cells that provide the structural and physiological support for hematopoietic cells. Additionally, the bone marrow stroma contains cells with a stem-cell-like character that allows them to differentiate into bone, cartilage, adipocytes, and hematopoietic supporting tissues. Several experimental approaches have been used to characterize the development and functional nature of these cells in vivo and their differentiating potential in vitro. In vivo, presumptive osteogenic precursors have been identified by morphologic and immunohistochemical methods. In culture, the stromal cells can be separated from hematopoietic cells by their differential adhesion to tissue culture plastic and their prolonged proliferative potential. In cultures generated from single-cell suspensions of marrow, bone marrow stromal cells grow in colonies, each derived from a single precursor cell termed the colony-forming unit-fibroblast. Culture methods have been developed to expand marrow stromal cells derived from human, mouse, and other species. Under appropriate conditions, these cells are capable of forming new bone after in vivo transplantation. Various methods of cultivation and transplantation conditions have been studied and found to have substantial influence on the transplantation outcome The finding that bone marrow stromal cells can be manipulated in vitro and subsequently form bone in vivo provides a powerful new model system for studying the basic biology of bone and for generating models for therapeutic strategies aimed at regenerating skeletal elements.

scholarly journals Hypoxic culture and in vivo inflammatory environments affect the assumption of pericyte characteristics by human adipose and bone marrow progenitor cells

2011 ◽  
Vol 301 (6) ◽  
pp. C1378-C1388 ◽  
Author(s):  
Peter J. Amos ◽  
Carolyn L. Mulvey ◽  
Scott A. Seaman ◽  
Joseph Walpole ◽  
Katherine E. Degen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Stromal Cells ◽  
Cell Types ◽  
Angiogenic Growth Factors ◽  
Adipose Derived Stromal Cells ◽  
Angiogenic Proteins ◽  
First Time

Previous studies have shown that exposure to a hypoxic in vitro environment increases the secretion of pro-angiogenic growth factors by human adipose-derived stromal cells (hASCs) [Cao Y, et al., Biochem Biophys Res Commun 332: 370–379, 2005; Kokai LE, et al., Plast Reconstr Surg 116: 1453–1460, 2005; Park BS, et al., Biomed Res (Tokyo) 31: 27–34, 2010; Rasmussen JG, et al., Cytotherapy 13: 318–328, 2010; Rehman J, et al., Circulation 109: 1292–1298, 2004]. Previously, it has been demonstrated that hASCs can differentiate into pericytes and promote microvascular stability and maintenance during angiogenesis in vivo (Amos PJ, et al., Stem Cells 26: 2682–2690, 2008; Traktuev DO, et al., Circ Res 102: 77–85, 2008). In this study, we tested the hypotheses that angiogenic induction can be increased and pericyte differentiation decreased by pretreatment of hASCs with hypoxic culture and that hASCs are similar to human bone marrow-derived stromal cells (hBMSCs) in these regards. Our data confirms previous studies showing that hASCs: 1) secrete pro-angiogenic proteins, which are upregulated following culture in hypoxia, and 2) migrate up gradients of PDGF-BB in vitro, while showing for the first time that a rat mesenteric model of angiogenesis induced by 48/80 increases the propensity of both hASCs and hBMSCs to assume perivascular phenotypes following injection. Moreover, culture of both cell types in hypoxia before injection results in a biphasic vascular length density response in this model of inflammation-induced angiogenesis. The effects of hypoxia and inflammation on the phenotype of adult progenitor cells impacts both the therapeutic and the basic science applications of the cell types, as hypoxia and inflammation are common features of natural and pathological vascular compartments in vivo.

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