Although the unique role of hematopoietic stem cell (HSC) niche in hematopoiesis has long been recognized, unsuccessful isolation of intact niche units limited their in vitro study, manipulation, and therapeutic application. Here, we isolated cell complexes based on size fractionation from mouse bone marrow (BM), characterized the derived cells, and transplanted them to irradiated mice. These cell complexes were the origin of both BM mesenchymal stem cells and various hematopoietic lineages when kept in appropriate culture conditions. They also had the potential of recruiting circulating HSC. Intraperitoneal transplantation of these structures into irradiated mice not only showed long-lasting hematopoietic multilineage reconstitution, but also could recover the stromal cells of BM. In conclusion, this study for the first time provides evidences on the feasibility and efficacy of transplantation of HSC in association with their native specialized microenvironment. As the molecular cross-talk between HSC and niche is crucial for their proper function, the proposed method could be considered as a novel hematopoietic transplantation strategy.
Get full access to this article
View all access options for this article.
References
1.
SchofieldR. 1978. The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells, 4:7–25.
ZhangJ, NiuC, YeL, HuangH, HeX, TongWG, RossJ, HaugJ, JohnsonTet al. 2003. Identification of the haematopoietic stem cell niche and control of the niche size. Nature, 425:836–841.
4.
KielMJ, YilmazOH, IwashitaT, TerhorstC, MorrisonSJ. 2005. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell, 121:1109–1121.
Mendez-FerrerS, MichurinaTV, FerraroF, MazloomAR, MacarthurBD, LiraSA, ScaddenDT, Ma'ayanA, EnikolopovGN, FrenettePS. 2010. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature, 466:829–834.
7.
MugurumaY, YahataT, MiyatakeH, SatoT, UnoT, ItohJ, KatoS, ItoM, HottaT, AndoK. 2006. Reconstitution of the functional human hematopoietic microenvironment derived from human mesenchymal stem cells in the murine bone marrow compartment. Blood, 107:1878–1887.
8.
UccelliA, MorettaL, PistoiaV. 2008. Mesenchymal stem cells in health and disease. Nat Rev Immunol, 8:726–736.
9.
JonesDL, WagersAJ. 2008. No place like home: anatomy and function of the stem cell niche. Nat Rev Mol Cell Biol, 9:11–21.
10.
PurtonLE, ScaddenDT. 2008. The hematopoietic stem cell niche. StemBook.
11.
AhmadbeigiN, SoleimaniM, GheisariY, VaseiM, AmanpourS, BagherizadehI, ShariatiSA, AzadmaneshK, AminiSet al. 2011. Dormant phase and multinuclear cells: two key phenomena in early culture of murine bone marrow mesenchymal stem cells. Stem Cells Dev, 20:1337–1347.
12.
Denning-KendallP, SinghaS, BradleyB, HowsJ. 2003. Cytokine expansion culture of cord blood CD34+ cells induces marked and sustained changes in adhesion receptor and CXCR4 expressions. Stem Cells, 21:61–70.
13.
GerdesAJ, StorbR. 1970. The repopulation of irradiated bone marrow by the infusion of stored autologous marrow. Radiology, 94:441–445.
14.
LawlerM, LocasciulliA, LongoniD, SchiroR, McCannSR. 2002. Leukaemic transformation of donor cells in a patient receiving a second allogeneic bone marrow transplant for severe aplastic anaemia. Bone Marrow Transplant, 29:453–456.
Le BlancK, FrassoniF, BallL, LocatelliF, RoelofsH, LewisI, LaninoE, SundbergB, BernardoMEet al. 2008. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet, 371:1579–1586.
17.
BallLM, BernardoME, RoelofsH, LankesterA, CometaA, EgelerRM, LocatelliF, FibbeWE. 2007. Cotransplantation of ex vivo expanded mesenchymal stem cells accelerates lymphocyte recovery and may reduce the risk of graft failure in haploidentical hematopoietic stem-cell transplantation. Blood, 110:2764–2767.
18.
MouiseddineM, FrancoisS, SemontA, SacheA, AllenetB, MathieuN, FrickJ, ThierryD, ChapelA. 2007. Human mesenchymal stem cells home specifically to radiation-injured tissues in a non-obese diabetes/severe combined immunodeficiency mouse model. Br J Radiol, 80,Spec No 1:S49–S55.
19.
PeisterA, MelladJA, LarsonBL, HallBM, GibsonLF, ProckopDJ. 2004. Adult stem cells from bone marrow (MSCs) isolated from different strains of inbred mice vary in surface epitopes, rates of proliferation, and differentiation potential. Blood, 103:1662–1668.
20.
GheisariY, AzadmaneshK, AhmadbeigiN, NassiriSM, GolestanehAF, NaderiM, VaseiM, ArefianE, Mirab-SamieeSet al. 2012. Genetic modification of mesenchymal stem cells to overexpress CXCR4 and CXCR7 does not improve the homing and therapeutic potentials of these cells in experimental acute kidney injury. Stem Cells Dev, 21:2969–2980.
BlazsekI, ChagraouiJ, PeaultB. 2000. Ontogenic emergence of the hematon, a morphogenetic stromal unit that supports multipotential hematopoietic progenitors in mouse bone marrow. Blood, 96:3763–3771.
23.
BlazsekI, LiuXH, AnjoA, QuittetP, ComissoM, Kim-TrianaB, MissetJL. 1995. The hematon, a morphogenetic functional complex in mammalian bone marrow, involves erythroblastic islands and granulocytic cobblestones. Exp Hematol, 23:309–319.
24.
BlazsekI, MissetJL, BenavidesM, ComissoM, RibaudP, MatheG. 1990. Hematon, a multicellular functional unit in normal human bone marrow: structural organization, hemopoietic activity, and its relationship to myelodysplasia and myeloid leukemias. Exp Hematol, 18:259–265.
25.
NoltaJA, HanleyMB, KohnDB. 1994. Sustained human hematopoiesis in immunodeficient mice by cotransplantation of marrow stroma expressing human interleukin-3: analysis of gene transduction of long-lived progenitors. Blood, 83:3041–3051.
26.
DaoMA, PepperKA, NoltaJA. 1997. Long-term cytokine production from engineered primary human stromal cells influences human hematopoiesis in an in vivo xenograft model. Stem Cells, 15:443–454.
27.
JinJD, WangHX, XiaoFJ, WangJS, LouX, HuLD, WangLS, GuoZK. 2008. A novel rich source of human mesenchymal stem cells from the debris of bone marrow samples. Biochem Biophys Res Commun, 376:191–195.
28.
WangL, BeneditoR, BixelMG, ZeuschnerD, StehlingM, SavendahlL, HaighJJ, SnippertH, CleversHet al. 2013. Identification of a clonally expanding haematopoietic compartment in bone marrow. EMBO J, 32:219–230.
29.
AhmadbeigiN, SoleimaniM, BabaeijandaghiF, MortazaviY, GheisariY, VaseiM, AzadmaneshK, RostamiS, ShafieeA, NardiNB. 2012. The aggregate nature of human mesenchymal stromal cells in native bone marrow. Cytotherapy, 14:917–924.
30.
Castro-MalaspinaH, GayRE, ResnickG, KapoorN, MeyersP, ChiarieriD, McKenzieS, BroxmeyerHE, MooreMA. 1980. Characterization of human bone marrow fibroblast colony-forming cells (CFU-F) and their progeny. Blood, 56:289–301.
31.
BruderSP, FinkDJ, CaplanAI. 1994. Mesenchymal stem cells in bone development, bone repair, and skeletal regeneration therapy. J Cell Biochem, 56:283–294.
32.
CampagnoliC, RobertsIA, KumarS, BennettPR, BellantuonoI, FiskNM. 2001. Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. Blood, 98:2396–2402.
33.
HernigouP, PoignardA, BeaujeanF, RouardH. 2005. Percutaneous autologous bone-marrow grafting for nonunions. Influence of the number and concentration of progenitor cells. J Bone Joint Surg Am, 87:1430–1437.
34.
ProckopDJ, AziziSA, ColterD, DigirolamoC, KopenG, PhinneyDG. 2000. Potential use of stem cells from bone marrow to repair the extracellular matrix and the central nervous system. Biochem Soc Trans, 28:341–345.
35.
WexlerSA, DonaldsonC, Denning-KendallP, RiceC, BradleyB, HowsJM. 2003. Adult bone marrow is a rich source of human mesenchymal “stem” cells but umbilical cord and mobilized adult blood are not. Br J Haematol, 121:368–374.
36.
CarrionB, HuangCP, GhajarCM, KachgalS, KniazevaE, JeonNL, PutnamAJ. 2010. Recreating the perivascular niche ex vivo using a microfluidic approach. Biotechnol Bioeng, 107:1020–1028.
37.
ChoiK, KennedyM, KazarovA, PapadimitriouJC, KellerG. 1998. A common precursor for hematopoietic and endothelial cells. Development, 125:725–732.
38.
NaveirasO, NardiV, WenzelPL, HauschkaPV, FaheyF, DaleyGQ. 2009. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature, 460:259–263.
39.
OhlsteinB, KaiT, DecottoE, SpradlingA. 2004. The stem cell niche: theme and variations. Curr Opin Cell Biol, 16:693–699.
40.
Lo CelsoC, FlemingHE, WuJW, ZhaoCX, Miake-LyeS, FujisakiJ, CoteD, RoweDW, LinCP, ScaddenDT. 2009. Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche. Nature, 457:92–96.
41.
DominiciM, RasiniV, BussolariR, ChenX, HofmannTJ, SpanoC, BernabeiD, VeronesiE, BertoniFet al. 2009. Restoration and reversible expansion of the osteoblastic hematopoietic stem cell niche after marrow radioablation. Blood, 114:2333–2343.
42.
CzechowiczA, KraftD, WeissmanIL, BhattacharyaD. 2007. Efficient transplantation via antibody-based clearance of hematopoietic stem cell niches. Science, 318:1296–1299.
43.
CorreJ, MahtoukK, AttalM, GadelorgeM, HuynhA, Fleury-CappellessoS, DanhoC, LaharragueP, KleinB, RemeT, BourinP. 2007. Bone marrow mesenchymal stem cells are abnormal in multiple myeloma. Leukemia, 21:1079–1088.
PottenCS, LoefflerM. 1990. Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. Development, 110:1001–1020.
46.
LevyV, LindonC, HarfeBD, MorganBA. 2005. Distinct stem cell populations regenerate the follicle and interfollicular epidermis. Dev Cell, 9:855–861.
47.
Di MaggioN, PiccininiE, JaworskiM, TrumppA, WendtDJ, MartinI. 2011. Toward modeling the bone marrow niche using scaffold-based 3D culture systems. Biomaterials, 32:321–329.
48.
YoshimotoM, ShinoharaT, HeikeT, ShiotaM, Kanatsu-ShinoharaM, NakahataT. 2003. Direct visualization of transplanted hematopoietic cell reconstitution in intact mouse organs indicates the presence of a niche. Exp Hematol, 31:733–740.
49.
IkeharaS. 2005. Intra-bone marrow-bone marrow transplantation: a new strategy for treatment of stem cell disorders. Ann N Y Acad Sci, 1051:626–634.
50.
KushidaT, InabaM, HishaH, IchiokaN, EsumiT, OgawaR, IidaH, IkeharaS. 2001. Intra-bone marrow injection of allogeneic bone marrow cells: a powerful new strategy for treatment of intractable autoimmune diseases in MRL/lpr mice. Blood, 97:3292–3299.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
