Small-sized adult bone marrow cells isolated by counterflow centrifugal elutriation and depleted of lineage markers (Fr25lin−) have the capacity to differentiate into insulin-producing cells and stabilize glycemic control. This study assessed competitive migration of syngeneic stem cells to the bone marrow and islets in a murine model of chemical diabetes. VLA-4 is expressed in ∼25% of these cells, whereas CXCR4 is not detected, however, it is transcriptionally upregulated (6-fold). The possibility to enrich stem cells by a bone marrow homing (BM-H) functional assay was assessed in sequential transplants. Fr25lin− cells labeled with PKH26 were grafted into primary myeloablated recipients, and mitotically quiescent Fr25lin−PKHbright cells were sorted from the bone marrow after 2 days. The contribution of bone marrow-homed stem cells was remarkably higher in secondary recipients compared to freshly elutriated cells. The therapeutic efficacy was further increased by omission of irradiation in the secondary recipients, showing a 25-fold enrichment of islet-reconstituting cells by the bone marrow homing assay. Donor cells identified by the green fluorescent protein (GFP) and a genomic marker in sex-mismatched transplants upregulated PDX-1 and produced proinsulin, affirming the capacity of BM-H cells to convert in the injured islets. There was no evidence of transcriptional priming of freshly elutriated subsets to express PDX-1, insulin, and other markers of endocrine progenitors, indicating that the bone marrow harbors stem cells with versatile differentiation capacity. Affinity to the bone marrow can be used to enrich stem cells for pancreatic regeneration, and reciprocally, conditioning reduces the competitive incorporation in the injured islets.
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References
1.
SharkisSJ, CollectorMI, BarberJP, ValaMS and JonesRJ. (1997). Phenotypic and functional characterization of the hematopoietic stem cell. Stem Cells, 15 (Suppl 1):41–45.
2.
SharkisSJ, NeutzelS and CollectorMI. (2001). Phenotype and function of hematopoietic stem cells. Ann N Y Acad Sci, 938:191–195.
3.
JuopperiTA, SchulerW, YuanX, CollectorMI, DangCV and SharkisSJ. (2007). Isolation of bone marrow-derived stem cells using density-gradient separation. Exp Hematol, 35:335–341.
4.
JonesRJ, CelanoP, SharkisSJ and SensenbrennerLL. (1989). Two phases of engraftment established by serial bone marrow transplantation in mice. Blood, 73:397–401.
5.
KrauseDS, TheiseND, CollectorMI, HenegariuO, HwangS, GardnerR, NeutzelS and SharkisSJ. (2001). Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell, 105:369–377.
6.
JangYY, CollectorMI, BaylinSB, DiehlAM and SharkisSJ. (2004). Hematopoietic stem cells convert into liver cells within days without fusion. Nat Cell Biol, 6:532–539.
7.
IskovichS, Goldenberg-CohenN, SteinJ, YanivI, FabianI and AskenasyN. (2012). Elutriated stem cells derived from the adult bone marrow differentiate into insulin-producing cells in vivo and reverse chemical diabetes. Stem Cells Dev, 21:86–96.
8.
Goldenberg-CohenN, Avraham-LubinBC, SadikovT, GoldsteinRS and AskenasyN. (2012). Primitive stem cells derived from bone marrow express glial and neuronal markers and support revascularization in injured retina exposed to ischemic and mechanical damage. Stem Cells Dev, 21:1488–1500.
IskovichS, Goldenberg-CohenN, SadikovT, YanivI, SteinJ and AskenasyN. (2014). Two distinct mechanisms of bone marrow cell involvement in islet remodeling: neogenesis of insulin producing cells and support of islet recovery. Cell Transplant, 24:879–890.
11.
LanzkronSM, CollectorMI and SharkisSJ. (1999). Hematopoietic stem cell tracking in vivo: a comparison of short-term and long-term repopulating cells. Blood, 93:1916–1921.
12.
YanF, CollectorMI, TyszkoS and SharkisSJ. (2003). Using divisional history to measure hematopoietic stem cell self-renewal and differentiation. Exp Hematol, 31:56–64.
13.
LanzkronSM, CollectorMI and SharkisSJ. (1999). Homing of long-term and short-term engrafting cells in vivo. Ann N Y Acad Sci, 872:48–56.
14.
JuopperiTA and SharkisSJ. (2008). Isolation of quiescent murine hematopoietic stem cells by homing properties. Methods Mol Biol, 430:21–30.
15.
JangYY and SharkisSJ. (2005). Stem cell plasticity: a rare cell, not a rare event. Stem Cell Rev, 1:45–51.
16.
IskovichS, KaminitzA, Pearl-YafeM, MizrahiK, SteinJ, YanivI and AskenasyN. (2007). Participation of adult bone marrow-derived stem cells in pancreatic regeneration: neogenesis versus endogenesis. Curr Stem Cell Res Ther, 2:272–279.
17.
Pearl-YafeM, SteinJ, YolcuES, FarkasDL, ShirwanH, YanivI and AskenasyN. (2007). Fas transduces dual apoptotic and trophic signals in hematopoietic progenitors. Stem Cells, 25:3194–3203.
Goldenberg-CohenN, Avraham-LubinBC, SadikovT and AskenasyN. (2014). Effect of co-administration of neuronal growth factors on neuroglial differentiation of bone marrow-derived stem cells in the ischemic retina. Invest Ophthalmol Vis Sci, 55:502–512.
20.
Avraham-LubinBC, Goldenberg-CohenN, SadikovT and AskenasyN. (2012). VEGF induces neuroglial differentiation in bone marrow-derived stem cells and promotes microglia conversion following mobilization with GM-CSF. Stem Cell Rev, 8:1199–1210.
21.
AskenasyN, YolcuES, ShirwanH, SteinJ, YanivI and FarkasDL. (2003). Characterization of adhesion and viability of early seeding hematopoietic cells in the host bone marrow in vivo and in situ. Exp Hematol, 31:1292–1300.
22.
LinnT, StrateC, FederlinK and PapaccioG. (1994). Intercellular adhesion molecule-1 (ICAM-1) expression in the islets of the non-obese diabetic and low-dose streptozocin-treated mouse. Histochemistry, 102:317–321.
23.
KayaliAG, Van GunstK, CampbellIL, StotlandA, KritzikM, LiuG, Flodström-TullbergM, ZhangYQ and SarvetnickN. (2003). The stromal cell-derived factor-1alpha/CXCR4 ligand-receptor axis is critical for progenitor survival and migration in the pancreas. J Cell Biol, 163:859–869.
24.
HuangY, KuciaM, HussainLR, WenY, XuH, YanJ, RatajczakMZ and IldstadST. (2010). Bone marrow transplantation temporarily improves pancreatic function in streptozotocin-induced diabetes: potential involvement of very small embryonic-like cells. Transplantation, 89:677–685.
25.
PonomaryovT, PeledA, PetitI, TaichmanRS, HablerL, SandbankJ, Arenzana-SeisdedosF, MagerusA, CaruzA, et al. (2000). Induction of the chemokine stromal-derived factor-1 following DNA damage improves human stem cell function. J Clin Invest, 106:1331–1339.
26.
LeeVM and StoffelM. (2003). Bone marrow: an extra-pancreatic hideout for the elusive pancreatic stem cell?. J Clin Invest, 111:799–801.
27.
KuciaM, RecaR, JalaVR, DawnB, RatajczakJ and RatajczakMZ. (2005). Bone marrow as a home of heterogenous populations of nonhematopoietic stem cells. Leukemia, 19:1118–1127.
28.
AskenasyN and FarkasDL. (2003). In vivo imaging studies of the effect of recipient conditioning, donor cell phenotype and antigen disparity on homing of haematopoietic cells to the bone marrow. Br J Haematol, 120:505–515.
29.
Pearl-YafeM, YolcuES, SteinJ, KaplanO, ShirwanH, YanivI and AskenasyN. (2007). Expression of Fas and Fas-ligand in donor hematopoietic stem and progenitor cells is dissociated from the sensitivity to apoptosis. Exp Hematol, 35:1601–1612.
30.
AskenasyN and FarkasDL. (2002). Optical imaging of PKH-labeled hematopoietic cells in recipient bone marrow in vivo. Stem Cells, 20:501–513.
31.
OrkinSH and ZonLI. (2002). Hematopoiesis and stem cells: plasticity versus developmental heterogeneity. Nat Immunol, 3:323–328.
32.
PlettPA, FrankovitzSM and OrschellCM. (2003). Distribution of marrow repopulating cells between bone marrow and spleen early after transplantation. Blood, 102:2285–2291.
33.
RatajczakMZ, KimC, Janowska-WieczorekA and RatajczakJ. (2012). The expanding family of bone marrow homing factors for hematopoietic stem cells: stromal derived factor 1 is not the only player in the game. ScientificWorldJournal, 2012;2012:758512
34.
RennertRC, SorkinM, GargRK and GurtnerGC. (2012). Stem cell recruitment after injury: lessons for regenerative medicine. Regen Med, 7:833–850.
35.
PitchfordSC, FurzeRC, JonesCP, WengnerAM and RankinSM. (2009). Differential mobilization of subsets of progenitor cells from the bone marrow. Cell Stem Cell, 4:62–72.
36.
LapidK, ItkinT, D'UvaG, OvadyaY, LudinA, CaglioG, KalinkovichA, GolanK, PoratZ, ZolloM and LapidotT. (2013). GSK3β regulates physiological migration of stem/progenitor cells via cytoskeletal rearrangement. J Clin Invest, 123:1705–1717.
37.
HaiderHKh, JiangS, IdrisNM and AshrafM. (2008). IGF-1-overexpressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of SDF-1alpha/CXCR4 signaling to promote myocardial repair. Circ Res, 103:1300–1308.
38.
WelniakLA, KarasM, YakarS, AnverMR, MurphyWJ and LeRoithD. (2004). Effects of organ-specific loss of insulin-like growth factor-I production on murine hematopoiesis. Biol Blood Marrow Transplant, 10:32–39.
39.
ZisaD, ShabbirA, MastriM, TaylorT, AleksicI, McDanielM, SuzukiG and LeeT. (2011). Intramuscular VEGF activates an SDF1-dependent progenitor cell cascade and an SDF1-independent muscle paracrine cascade for cardiac repair. Am J Physiol Heart Circ Physiol, 301:H2422–H2432.
40.
StevensonKS, McGlynnL, HodgeM, McLindenH, GeorgeWD, DaviesRW and ShielsPG. (2009). Isolation, characterization, and differentiation of thy1.1-sorted pancreatic adult progenitor cell populations. Stem Cells Dev, 18:1389–1398.
41.
HunzikerE and SteinM. (2000). Nestin-expressing cells in the pancreatic islets of Langerhans. Biochem Biophys Res Commun, 271:116–119.
42.
LinHT, ChiouSH, KaoCL, ShyrYM, HsuCJ, TarngYW, HoLL, KwokCF and KuHH. (2006). Characterization of pancreatic stem cells derived from adult human pancreas ducts by fluorescence activated cell sorting. World J Gastroenterol, 12:4529–4535.
43.
KuciaM, RecaR, CampbellFR, Zuba-SurmaE, MajkaM, RatajczakJ and RatajczakMZ. (2006). A population of very small embryonic-like (VSEL) CXCR4(+)SSEA-1(+)Oct-4+ stem cells identified in adult bone marrow. Leukemia, 20:857–869.
44.
SuszynskaM, Zuba-SurmaEK, MajM, MierzejewskaK, RatajczakJ, KuciaM and RatajczakMZ. (2014). The proper criteria for identification and sorting of very small embryonic-like stem cells, and some nomenclature issues. Stem Cells Dev, 23:702–713.
45.
TaichmanRS, WangZ, ShiozawaY, JungY, SongJ, BalduinoA, WangJ, PatelLR, HavensAMet al. (2010). Prospective identification and skeletal localization of cells capable of multilineage differentiation in vivo. Stem Cells Dev, 19:1557–1570.
46.
RatajczakJ, Zuba-SurmaE, KlichI, LiuR, WysoczynskiM, GrecoN, KuciaM, LaughlinMJ and RatajczakMZ. (2011). Hematopoietic differentiation of umbilical cord blood-derived very small embryonic/epiblast-like stem cells. Leukemia, 25:1278–1285.
47.
HavensAM, ShiozawaY, JungY, SunH, WangJ, McGeeS, MishraA, TaichmanLS, DanciuT, et al. (2013). Human very small embryonic-like cells generate skeletal structures, in vivo. Stem Cells Dev, 22:622–630.
48.
KassmerSH, JinH, ZhangPX, BrusciaEM, HeydariK, LeeJH, KimCF and KrauseDS. (2013). Very small embryonic-like stem cells from the murine bone marrow differentiate into epithelial cells of the lung. Stem Cells, 31:2759–2766.
49.
ZiporiD. (2004). The nature of stem cells: state rather than entity. Nat Rev Genet, 5:873–878.
50.
AskenasyN, YanivI, SteinJ and SharkisSJ. (2006). Our perception of developmental plasticity: esse est percipi (to be is to be perceived)?. Curr Stem Cell Res Ther, 1:85–94.
51.
LeeRH, SeoMJ, RegerRL, SpeesJL, PulinAA, OlsonSD and ProckopDJ. (2006). Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice. Proc Natl Acad Sci U S A, 103:17438–17443.
52.
MoriscotC, de FraipontF, RichardMJ, MarchandM, SavatierP, BoscoD, FavrotM and BenhamouPY. (2005). Human bone marrow mesenchymal stem cells can express insulin and key transcription factors of the endocrine pancreas developmental pathway upon genetic and/or microenvironmental manipulation in vitro. Stem Cells, 23:594–603.
53.
KarnieliO, Izhar-PratoY, BulvikS and EfratS. (2007). Generation of insulin-producing cells from human bone marrow mesenchymal stem cells by genetic manipulation. Stem Cells, 25:2837–2844.
54.
WuX, LuoY, ChenJ, PanR, XiangB, DuX, XiangL, ShaoJ and XiangC. (2014). Transplantation of human menstrual blood progenitor cells improves hyperglycemia by promoting endogenous progenitor differentiation in type 1 diabetic mice. Stem Cells Dev, 23:1245–1257.
55.
ParsonsJA, BartkeA and SorensonRL. (1995). Number and size of islets of Langerhans in pregnant, human growth hormone-expressing transgenic, and pituitary dwarf mice: effect of lactogenic hormones. Endocrinology, 136:2013–2021.
56.
JoJ, ChoiMY and KohDS. (2007). Size distribution of mouse Langerhans islets. Biophys J, 93:2655–2666.
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