116 Plenary Presentations

[hat communication with the micro-environment in rurn dete rmines the self­

renewal and diffe rentiati on programs.

Amo ng epitheli al ce ll s, inte ractio ns be tween ce lls is medi ated th rough fo rm ation

of junctional complexes. Data fro m the lite ra tu re and o ur pre li min ary experi ments

also supporred this norion, and showed th at a specifi c diffe renti atio n program might

be switched on after juncti onal compl exes are form ed with the surroundings. We

have evidence th at these might also be responsible for com munication between

HSC and the ir ni che.

References Weissrnan IL. T ranslati ng stem and progeni tor cell biology to the clini c: barrie rs

and opportunities. Science 2000;287: 1442 - 6.

Siminovitch L, McCulloch EA, T iIlJE. T he d istribution of colon y-forming cells

among spl een colonies. J Cell Comp Physiol 1963;62:323 - 7.

Becker A, McCulloch EA, Till J E. Cytological demonstration of the clonal

nature of spleen colonies de ri ved from transpl anted mouse marrow cell s. Nal llre

1963; 197:452 - 5.

4 Fuchs E, Segre J A. Stem cell s: a new lease on li fe. Cell 2000;100: 143- 55.

Kiirbling M, Dorken B, Ho AD et al. Autologous transpl antati on of blood­

derived hemopoieric stem cells afte r myeloabl ative therapy in a patient with

Burkitt's lym phoma. Blood 1986;67:529- 32.

H aas R, Ho AD, Bredrhauer W et al . Successful autologous transpl antation of

blood stem cells mobilized with recombin ant human granulocyte- macroph age

colony-stimul ating factor. Exp Hematol 1990; 18:94 - 8.

La ne TA, Law P, M aru yama M et al . Harvesting and enri chment of

he matopo ie tic progeni tor cell s mobili zed into the peripheral blood of norm al

do nors by granulocyte macroph age-colo ny stimulating facto r (G M-CS F) o r G­

CSF: Potenti al ro le in all ogeneic marrow transpl antation. Blood 1995;85:275 - 82.

Pereira R F, H alford KW, O ' Hara MD er al. Cultured adherent cells from marrow

can serve as long- lasting precursor cells for bone, cartil age, and lung in

irradiated mice. Proc Nat! Acad Sci USA 1995;92:4857 - 6 1.

9 Pittenger M F, M ackay AM, Beck SC et at. Multilineage potenti al of adult hum an

mesenchymal stem cell s. Scimce 1999;284: 143- 7.

10 Emura M, Ochiai A, Horino M er al. Development of myofibrobl asts from

human bone marrow mesenchymal ste rn cells coculrured with hu man colon

carcinoma cells and TG F beta I. 111 Vitr Cell De-u Bioi 2000;36:77 - 80.

11 Lagasse E, Connors H, AI- Dh alimy M et al. Purified hematopoie ti c stem cells

can di fferenti ate in to hepatocytes in vivo. Nat Med 2000;6:1229- 34.

12 Orlic 0, Kajstura J, C himenti S et al. Bone marrow cells regenerate infa rcted

myocardium. Nature 2001 ;410:701 - 5.

13 Kocher AA, Schuster MD, Szabo lcs MJ et al. Neovasculari za tio n of ischemi c

m yoca rdium by hum an bone-marrow-derived angiobl asts prevents cardio myo­

cyte apoptosis, reduces remodeling and improves cardiac fun ction. Nat Med

200 1;7:430-6.

14 Kiger AA, White-Coope r H , Julle r M T Somatic suppOrt cells restrict germline

stem cell self- renewal and promote diffe renti ation. Nature 2000;407:750 - 4.

15 Punzel M, Moore KA, Lemischka fR, Verfa illie CM. T he type of st romal feeder

used in limiting dilution assays influences frequency and maintenan ce assess­

ment of hum an long- te rm culture initi ating cell s. Leukemia 1999; 13: 92 - 7.

16 Huang 5, Law P, Francis K et 01. Symmetry of initi al cell divisions among

primitive hematopoietic p rogenitors is independent of o ntogenic age and

regulato ry molecules. Blood 1999;2:595 - 604.

17 Pun zel M, Zh ang T, Liu 0 et al . Functional analys is of initi al cell divisions

defines the subsequent fate of individu al human C D 34 + / C D 38 - cells. Exp

Hematol In press.

PLASTICITY OF BONE MARROW-DERIVED STEM CELLS

Di ane S Krause

Recent discoveries in multiple laboratories, including my own, have shown that BM ­

derived stem cells can migrate into a variety of diffe rent ti ssues and diffe rentiate

into nonhematopoie tic epithelial or parenchymal cells. Standard paradigms of cell

di ffe rentiative potenti al need to be broadened to accommod ate these findin gs.

Several recent reports suggest th at the re is far more pl as ticity th an previously

believed in the developmental potenti al of many different adul t cell types.

Recentl y, we and others showed th at a BM popul ation enriched for HSC can

di fferenti ate into mature hepatocytes in the liver of rodents, and this diffe renti ation

of BM cells into mature cells of the liver also occurs in human. Other examples of

this surprising pl as ticity are appearing rapidl y in the scientific lite rature, includ ing,

for example, the ill vivo regeneratio n of murine skeletal muscle cells fro m BM cells,

and the reconstitution of BM from cul tu red brain and gli al ce lls. The bound aries

dete rmined by embryologic tril amin ar origin are the refore not maintained in the

adul t.

We have shown th at ra re cells which home to BM ca n lo ng-term reconstitute the

hemaropoietic system o f primary and second ary recipients. During the homing,

C D34 and SCA- I expression increases unique ly o n cells that home to marrow.

T hese adult BM cells have tremendous diffe rentiative capacity, as they can also

diffe rentia te into epithe li al cells of the live r, lung, gastrointestin al tract, and skin.

Th is fi ndi ng may contri bute to clini cal treatment of genetic disease or ti ssue repair.

When female mice are transpl anted with male BM and then exposed to va rious

fo rms of tissue d amage, those forms of injury that more profoundl y affec t the ability

of the intra-organ stem cells to fun ction are more like ly to lead to a recruitment of

marrow-deri ved cells as part of the ir repaired epi the li al layers. For exa mple, the

cholangiocyte toxin DA PJ\1, which causes peri portal necrosis in rhe liver, leads to a

5 - 20 fold in crease in the number of marrow-derived hepatocytes, whereas removal

of 2/ 3 o f the liver does not cause recruitment of marrow-derived cell s during

regrowth of the li ver to its origin al mass.

Brief bibliography on plasticity 1 Abkow itz J L. Ca n human hematopoieti c stem cells become skin , gut, or liver

cell s? N ElIgl] Med 2002;346:770 - 2.

Fe rrari G, C usella- DeAngelis G, Coletta M et al. Muscle regeneration by bone

marrow-deri ved myogenic progeni tors. Scie1lce 1998;279: 1528 - 30.

G ussoni E, Soneoka V, Strickl and C D et al . Dystrophin expression in the mdx

mouse restored by stem cell transpl anta tion. Natllre 1999;401 :390 - 4.

4 Imasawa T, Utsunomi ya Y, Kawamura T et al. The potenti al of bone marrow­

derived cells to differentiate to glomerul ar mesangial cell s. J Am Soc Nepbrol

2001 ;12: 140 1- 9.

5 J ackson KA, M ajka SM, Wang H et al. Regene rati on of ischemic card iac muscle

and vascular endothelium by adult stem cells. J C/ill Invert 2001 ;107:1395 - 402.

6 Kawada H, Ogawa M. Bone marrow o rigin of hematopoietic progenitors and

stem cells in murine muscle. Blood 2001 ;98:2008- 13.

Korbling M , Katz RL, Kh anna A et al. Hepatocytes and epitheli al cells of donor

origin in recipients of peripheral-blood stem cell s. N Engl J Med 2002;346:738-

46.

Kotton ON, M a BV, Cardoso WV et al. Bone marrow-derived cells as progenitors

of lung alveolar epi thelium. De-ue/opment 2001 ;128:5 181 - 8.

9 Krause OS, Theise N O, Collector Mf et at. Mult i-organ, multi - lineage

engraftm ent by a single bone marrow-derived stem cell. Cell 2001 ;105:369 - 77.

10 M cKinney-Freeman SL, J ackson KA, C am argo FD et at. Muscl e-de rived

hemaropo ie tic stem cells are hematopoietic in origin. Proe Nad Aead Sci USA

2002;99: 1341 - 6.

11 Orli c 0 , Kajstura J , C himenti 5 et al. Mobili zed bone marrow cells repair the

infarcted heart, improving fun cti on and surviva l. Proe Nat! Acad Sei USA

200 I ;98: I 0344 - 9.

12 Pe te rsen BE, Bowen WC, Patrene KD etal. Bo ne marrow as a potential source of

hepatic oval cells. Scietlce 1999;284: 1168 - 70.

13 Poulsom R, Forbes SJ , Hodivala- Dilke K et al. Bone marrow contributes to renal

parenchymal turnover and regeneration. J Patbol 2001 ; 195:229 - 35.

14 P rille r J , Persons DA, Klett FF et al. Neogenesis of cerebe ll ar Purkinje neurons

from gene- marked bone marrow cells in vivo. J Cell Bioi 2001 ;155:733-8.

15 ~aini F, Urbane k K, Beltrami AP et al. C hime rism of the transpl anted heart. N Engl J Med 2002;346:5 - 15.

16 T heise N O, Badve 5, Saxen a R et al . Deriva tion of he patocytes from bone

marrow cells in mice after radiation- induced myelo abl ation. Hepatology

2000;3 1:235- 40.

17 T heise ND, N imm akayalu M, G ardner R et al. Liver from bone marrow in

humans. Hepatology 2000;32: 11 - 6.

BLOOD STEM CELLS REPAIR MYOCARDIAL INFARCTS

Donald Orlic

The BM stem cells (BMSCs) of adult mice are be lieved to have the potential to

generate no nhematopoie tic ce ll types, including epithe lial cell s, ske letal muscle

cells, hepatocytes, osteocytes, and neural cells. This newly discovered ability of stem

cells is refe rred to as p lasticity. We have investigated the potential of BMSCs to

di fferentiate into cardiac myocytes in m yocardium th at has been d amaged by

ischemi a.

Infarcts were produced in the left ventricl e of adult female mi ce by liga tion of the

left coron ary arte ry (LCA). T he infa rcts were treated wi th Lin - c- kit + cells

isolated from BM from adul t male transgenic mice that expressed enhanced green