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发表于 2009-3-5 10:35 |只看该作者 |倒序浏览 |打印

Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, California, USA0 e# j. h4 ?) Q& V+ K9 P6 X; o# _: y: G
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Key Words. Adult stem cells ? Bone marrow ? Hematopoietic stem cells ? Muscle stem cells ? Somatic stem cell transdifferentiation. ~$ z" Q+ C) s  F2 `

Correspondence: Amy J. Wagers, Ph.D., Joslin Diabetes Center, 1 Joslin Place, Boston, Massachusetts 02215, USA. Telephone: 617-732-2590; Fax: 617-732-2593; e-mail: amy.wagers@joslin.harvard.ed" C, _/ ]- M" U3 F/ K3 i0 h  r8 x* G

ABSTRACT
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Stem cells are primitive, self-renewing cells that in many adult tissues function to maintain tissue homeostasis and to regenerate damaged tissue following injury . In postnatal skeletal muscle, repair of tissue damage is thought to be mediated by tissue-resident satellite cells, located beneath the basal lamina of multinucleated myofibers . However, several recent reports  have suggested that adult skeletal muscle may additionally derive from bone marrow (BM) precursors and have implicated hematopoietic stem cells (HSCs) or their progeny as possible candidates for this activity. Yet existing studies have not fully defined the dynamics of BM contribution to muscle, and it remains unclear whether transplanted cells home to muscle immediately after intravenous transfer or whether they may circulate in the bloodstream or engraft at other locations before being recruited to damaged tissue. Additionally, the biological processes that allow BM or HSC contributions to skeletal muscle are just beginning to be defined and may involve cell fusion , transdifferentiation, or differentiation from a pluripotent  or muscle-committed  stem or progenitor cell.
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We previously demonstrated that in irradiation-damaged tissues, single c-kit Thy1.1loLin–Sca-1  (KTLS)  HSCs can fully repopulate the hematolymphoid system but essentially do not contribute to any nonblood tissues . To extend these data to evaluate the possibility that selective pressure resulting from tissue damage may recruit HSCs or their progeny to nonhematopoietic cell fates, we now have tested the capacity of unfractionated BM cells or of prospectively isolated KTLS HSCs to contribute to muscle cell lineages after transplantation into irradiated adult or newborn mouse recipients. In addition, using a parabiotic mouse model, in which genetically distinct animals are surgically joined such that they develop a common, anastomosed vascular system , we have evaluated recruitment from circulation of cells capable of contributing to regenerating muscle. Together, these models allow the quantitative assessment of muscle descendants generated from BM, HSCs, or circulating cells during muscle growth, homeostasis, and repair.% G4 g5 s1 V1 ~4 T

MATERIALS AND METHODS
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To investigate potential contributions of BM cells or BM HSCs to the repair of damaged skeletal muscle, irradiated newborn or adult recipient mice were transplanted with highly purified KTLS HSCs or unfractionated BM cells isolated from ?-actin/GFP-expressing donors, and chimeric mice were subsequently injured by either single or repeated intramuscular injection of cardiotoxin or by mechanical crushing of the TS or TA muscles. Both BM- and HSC-transplanted animals showed roughly equivalent, stable, multilineage hematopoietic engraftment by GFP  cells before muscle injury (see Materials and Methods). Eight weeks after injury, injured and uninjured muscles were harvested and serial frozen sections were prepared and stained with anti-GFP and with antibodies recognizing the muscle-specific markers dystrophin, -actinin, or skeletal muscle myosin or the pan-hematopoietic marker CD45 . Donor contributions to muscle were identified as cells that expressed GFP, costained for muscle markers, and did not express CD45. In addition, to exclude autofluorescent cells and confirm GFP expression, GFP was visualized both by immunofluorescence and by immunohistochemistry.
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In adult animals transplanted with unfractionated BM cells, GFP  muscle fibers were observed in the skeletal muscle of a fraction of mice injured either once or repeatedly (Fig. 1). Although GFP  myofibers were never observed in uninjured TS muscles of BM-transplanted animals (n = 4; data not shown), GFP  muscle cells were present in both the TA (2 of 6 muscles analyzed) and the TS (15 of 19 muscles analyzed) of animals injured by crushing or cardiotoxin injection, indicating that tissue damage significantly increases the contribution of GFP  cells to muscle (p  .05), and overall the frequency of incorporation of GFP  myofibers in BM-transplanted mice was exceedingly rare (generally less than 0.4% of total myofibers). Transplantation of BM cells into newborn animals also did not enhance the ability of these cells to contribute to myofibers (Fig. 2). Although GFP  myofibers were never observed in the uninjured TS of BM-transplanted mice ( and data not shown), they were detected at a very low frequency in uninjured diaphragm (1 of 20 mice examined), PC (2 of 9 mice examined), and abdominal muscles (1 of 20 mice examined) (Figs. 1, 2). BM-derived contributions to myofibers were not enhanced after injection of BM cells directly into cardiotoxininjured TS muscle, as has been described previously , or by Cy/G-CSF–induced mobilization of HSCs and progenitor cells  in animals previously transplanted with unfractionated BM (data not shown). In particular, although Cy/G-CSF–treated animals displayed an approximate 30- to 50-fold increase in blood-borne HSCs at the time of muscle injury, they showed no significant increase in the frequency with which GFP  myofibers were found in the damaged muscle (0.03% GFP  myofibers, p > .05).( E5 D, T) o* f. {4 ^7 W

Figure 1. (A–C): Representative micrographs showing immunofluorescent and immunohistochemical analysis of serial frozen sections of cardiotoxin-injured (single injection) TS muscles from animals reconstituted as adults with either 100 c-kit Thy1.1loLin–Sca-1  HSCs (A) or 1 x 106 to 5 x 107 BM cells (B, C) from GFP-expressing donor mice. Hematopoietic chimerism was determined by flow cytometry >8 weeks after transplant, and for all transplanted animals, the percent of GFP  peripheral blood leukocytes was >90%. (A, B): Sections were analyzed for colocalization of muscle or hematopoietic markers (left column, -actinin , dystrophin , or CD45 ) with GFP (middle column). Fluorescence images are electronically merged in the right column (red, -actinin, dystrophin, or CD45, as indicated; green, GFP, blue, nuclear staining by Hoechst 33342). Immunohistochemical detection of GFP was also performed on serial sections (last row) to exclude potential autofluorescent cells. (C): Confocal analysis showing colocalization of GFP with -actinin in a second BM-transplanted mouse (red, -actinin; green, GFP; blue, Hoechst 33342). (D, E): Representative micrographs showing immunofluorescence analysis of serial frozen sections of injured TA and TS from animals reconstituted as adults with either BM (D) or HSCs (E) and injured by repeated injection of cardiotoxin (three times, once a week for 3 weeks). Harvested tissues were examined for GFP  donor cell incorporation 5 weeks after injury. Serial sections were analyzed for colocalization of antiskeletal muscle myosin (fast; shown alone in the first columns) with GFP (shown alone in the second columns). Fluorescence images are electronically merged in the third columns (red, antimyosin; green, GFP; blue, nuclear staining by Hoechst 33342); scale bar = 100 μm. All GFP  myofibers detected in the injured muscles of BM-transplanted mice and most GFP  myofibers in the injured muscles of HSC-transplanted animals expressed fast myosin (type II fibers) but not slow myosin (type I fibers). Two hybrid myofibers (of 35 GFP  fibers examined), expressing both fast and slow myosin, were detected in repeatedly injured TS muscles of HSC-transplanted animals; no hybrid fibers (of 48 GFP  fibers examined) were detected in BM-transplanted animals. (F): Quantification of skeletal muscle contributions by donor cells in HSC- or BM-transplanted animals to injured TA and TS muscles (injured either by crushing or by single injection  or triple intramuscular injection  of CDTX) and to uninjured abdominal muscle, diaphragm, and panniculus carnosus muscles. Data are presented as the frequency (%) of GFP  myofibers (number of GFP  fibers / total fibers examined) for each muscle examined; each point represents an individual mouse and muscle, with the average for each group indicated by a bar. The frequency of muscles in which GFP  myofibers were detected (frequency of chimerism = number of engrafted muscles / number of muscles examined) is also given. Differences in the frequency of GFP  myofibers detected in BM-transplanted versus HSC-transplanted mice were statistically significant (p

Figure 2. (A): Representative micrographs showing immunofluorescence analysis of frozen sections of cardiotoxin-injured TS muscles from animals reconstituted as newborns with GFP-expressing BM cells. Sections were analyzed by immunohistochemistry for GFP and by immunofluorescence for colocalization of GFP and -actinin (first column, GFP horseradish peroxidase; second column, GFP immunofluorescence; third column, -actinin; last column, electronically merged image with -actinin shown in red, GFP in green, and Hoechst 33342 in blue); scale bar = 100 μm. (B): Quantification of skeletal muscle contributions by donor cells in animals transplanted as newborns with HSCs or BM to injured TS muscles (injured by muscle crush or by single injection  of CDTX) and to uninjured abdominal muscle and diaphragm. Data are presented as the frequency (%) of GFP  myofibers (number of GFP  fibers / total fibers examined) for each muscle examined; each point represents an individual mouse and muscle, with the average for each group indicated by a bar. The frequency of muscles in which GFP  myofibers were detected (frequency of chimerism = number of engrafted muscles / number of muscles examined) is also given. The decrease in incorporation of GFP  fibers in injured TS muscles of mice transplanted with BM cells as newborns versus adults (Fig. 1) was statistically significant (p 4 T! ^5 Y6 F) {5 V5 T' i( A! A# V

As in BM-transplanted animals, we also observed incorporation of GFP  muscle fibers into skeletal muscle of a fraction of animals transplanted with purified KTLS HSCs. Although no donor contributions were detected in the TS of HSC-transplanted animals injured only once (0 of 10 adult recipients and 0 of 7 newborn recipients), repeated injury of the TS did allow the incorporation of donor markers into myofibers in a subset of transplanted mice (one of three recipients; p
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To demonstrate unequivocally that the GFP  myofibers found in damaged skeletal muscle of HSC-transplanted animals truly arise by incorporation of donor markers derived from KTLS HSCs, we also analyzed mice whose hematopoietic system had been highly reconstituted (>80% GFP  blood leukocytes) by a single GFP  KTLS HSC. In one such animal, although no GFP  myofibers were detected in singly injured TA (0 of 6,720 fibers examined) or TS (0 of 16,198 fibers examined) muscles, triple injury of either muscle on the contralateral leg did result in low-level incorporation (0.015%  of TA fibers examined and 0.033%  of TS fibers examined) of cells coexpressing GFP and skeletal muscle markers (Fig. 3)." G9 p+ z2 @. A! F, |

Figure 3. Analysis of muscle contributions in single KTLS HSC-reconstituted mice. Lethally irradiated adult nontransgenic recipient animals were reconstituted with a single GFP  KTLS HSC, together with 3 x 105 Sca-1–depleted nontransgenic bone marrow, as described previously . (A): Hematopoietic chimerism of PB leukocytes was analyzed by flow cytometry 11 months after transplant. Data are presented as a histogram of relative GFP fluorescence intensity for live-gated control, nontransgenic PB leukocytes (black line) or for live-gated PB leukocytes from a single HSC-reconstituted animal (green line). In this mouse, ~81% of PB leukocytes expressed GFP, including cells of both the lymphoid and myeloid lineages (data not shown). (B, C): Representative micrographs showing immunofluorescence analysis of frozen sections of triple-injured TA (B) or TS (C) muscles from the single HSC-reconstituted animal shown in (A). TA and TS muscles were injured by repeated injection of cardiotoxin (three times, once a week for 3 weeks) and examined for GFP  donor cell incorporation 5 weeks after injury. Serial sections were analyzed for colocalization of anti--actinin (shown alone in the first columns) with GFP (shown alone in the second columns). Fluorescence images are electronically merged in the third columns (red, anti-myosin; green, GFP; blue, nuclear staining by Hoechst 33342); scale bar = 100 μm. GFP  myofibers were detected at a frequency of 0.015% (2 of 13,498) in the triple-injured TA and 0.033% (4 of 12,052) in the triple-injured TS. No GFP  myofibers were detected in the TA or TS muscles of the contralateral leg, which were injected with cardiotoxin only once (data not shown). Abbreviations: GFP, green fluorescent protein; HSC, hematopoietic stem cell; KTLS, c-kit Thy1.1loLin–Sca-1 ; PB, peripheral blood; TA, tibialis anterior; TS, triceps surae.  q% p& G+ t# b
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In either BM-transplanted or HSC-transplanted animals, donor-derived GFP  muscle fibers detected in the TA or TS muscles occurred predominantly as single, isolated cells, were well integrated into the muscle tissue, and were otherwise indistinguishable from surrounding GFP– myofibers (Figs. 1–3). Most of these GFP  muscle fibers in both the TA and TS muscles were type II fibers, expressing fast, but not slow, skeletal muscle myosin (Fig. 1 and data not shown). Taken together, these data indicate that both BM and HSCs can contribute donor markers to injured and regenerating skeletal muscle. In addition, different muscles seem to differ both in the rate with which they incorporate HSC- or BM-derived markers into myofibers and in their requirement for acute muscle injury to evoke such contributions.
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HSCs, as well as some nonhematopoietic, tissue-specific progenitor cells, constitutively circulate in the bloodstream . To evaluate the possibility that HSC- or BM-derived cells, or circulating muscle progenitors, may be recruited to skeletal muscle from normal circulation in the absence of lethal irradiation and iatrogenic infusion of these cells, and thereby contribute to injured muscle, we used a parabiotic model in which two mice, one GFP  and one GFP–, were surgically joined such that they developed a common, anastomosed, circulatory system . In parabiotic mice, blood chimerism is detectable within 2–3 days of joining, reaches approximately 50% 8–10 days after parabiosis, and is maintained at this level thereafter . TS muscles of nontransgenic (GFP–) partners of parabiotic pairs were injured by crushing at the time of joining or by cardiotoxin injection 3–4 months after parabiosis. Eight weeks after injury, injured and uninjured muscles were harvested and analyzed for the presence of GFP  (partner marker ) myofibers. All injured parabiotic mice analyzed (five of five) incorporated GFP  myofibers at the site of injury in the TS, regardless of whether the injury occurred at the time of parabiosis or several months after parabiosis (Fig. 4). A cluster of GFP  myofibers was observed in one animal; however, most GFP  myofibers in injured parabiont muscle were single, isolated cells. Consistent with previous studies , no GFP  partner-derived myofibers were detected in uninjured muscles (diaphragm, abdominal, or TS) of parabiotic partners (Fig. 4). Thus, injury promotes contributions of circulating cells to muscle in parabiotic animals (p / q: m, B7 E& k+ W4 L( C- R
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Figure 4. Representative micrographs showing immunofluorescence analysis of frozen sections of cardiotoxin-injured (A, B) or crush-injured (C–E) TS muscles of parabiotic mice. (A): Cardiotoxin-injured TS from GFP transgenic partner of a parabiotic pair. (B): Cardiotoxin-injured TS from the non-transgenic partner of (A). (C): A cluster of GFP  myofibers in the crush-injured TS of a nontransgenic animal joined by parabiosis to a GFP transgenic partner. (D): Crush-injured TS from the BM-transplanted partner of a parabiotic pair. (E): Crush-injured TS from the untransplanted partner of (D). Sections were analyzed for colocalization of -actinin and GFP (left column, -actinin; middle column, GFP; right column, electronically merged image with -actinin shown in red, GFP in green, and Hoechst 33342 in blue). Scale bar = 100 μm. (F): Quantification of skeletal muscle contributions by partner-derived cells in parabiotic animals to injured TS muscles (injured by muscle crush or by single injection  of CDTX) and to uninjured AB and DIA. Data are presented from the nontransgenic partners of GFP transgenic mice (GFP) and from the nontransgenic partners of mice previously transplanted with GFP  BM cells (BMT) and are shown as the frequency (%) of GFP  myofibers (number of GFP  fibers / total fibers examined) for each muscle examined; each point represents an individual mouse and muscle, with the average for each group indicated by a bar. The frequency of muscles in which GFP  myofibers were detected (frequency of chimerism = number of engrafted muscles / number of muscles examined) is also given. Differences in the frequency of GFP  myofibers detected in parabiotic mice joined to GFP transgenic partners versus those joined to previously transplanted animals were not statistically significant (p > .05). Abbreviations: AB, abdominal muscle; BM, bone marrow; BMT, bone marrow transplanted; DIA, diaphragm; GFP, green fluorescent protein; TS, triceps surae.4 H, f: a( P1 r( O, e2 F* f, @
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To investigate the relationship between BM-derived and circulating myogenic cells, we also generated parabiotic pairs using two nontransgenic animals, one of which had previously undergone GFP  BM transplantation. The TS muscles of both animals were injured by crushing at the time of parabiosis and were analyzed 8 weeks later for the presence of GFP  myofibers. GFP  myofibers were found at low frequency in the injured TS muscles of both the BM-transplanted mice (three of three mice; data not shown) and their untransplanted partners (two of three mice; Fig. 4). In one pair, rare GFP  myofibers were also observed in the uninjured abdominal muscle of the BM-transplanted partner but were never found in uninjured muscle in untransplanted parabionts. Thus, these data indicate that the incorporation of genetic markers contained in BM-derived cells into muscle in response to injury can occur long after irradiation and transplantation of BM cells and that at least some circulating cells capable of contributing to skeletal muscle are BM-derived; nonetheless, it remains possible that distinct cell populations with identical or overlapping function may exist also in circulation.' t) \  r; s1 B' R( _
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The precise biological processes that allow BM or HSC contributions to skeletal muscle are clearly of interest in understanding this phenomenon and potentially could involve cell fusion , transdifferentiation, or differentiation from a pluripotent cell  or muscle-committed stem or progenitor cell . Therefore, to evaluate the relative importance of de novo myogenesis or cell fusion in the formation of BM- or HSC-derived GFP  myofibers, we developed an additional transgenic mouse model that ubiquitously expresses a spectrally distinct fluorescent protein (HcRed) from the ?-actin promoter (A. Terskikh et al., unpublished data) and transplanted these ?-actin/HcRed mice, which express the unique host-specific marker in 100% of skeletal myofibers, with GFP  BM or KTLS HSCs. We then analyzed skeletal myofibers in the TA and TS muscles of these mice after cardiotoxin-induced injury for possible coexpression of the donor-specific marker (GFP) and the host-specific marker (HcRed). All of the GFP  myofibers detected in the regenerating muscle of HcRed recipient mice transplanted with either GFP  unfractionated BM or KTLS HSC coexpressed GFP and HcRed, indicating that these fibers formed through cell fusion rather than de novo myogenesis (Fig. 5) and ruling out direct differentiation or transdifferentiation of BM cells or KTLS HSCs on their own into mature skeletal myofibers in these injury models.  P7 X5 u; R. b- n) E

Figure 5. Representative micrographs showing immunofluorescence analysis of frozen sections of injured TA (A, C) or TS (B) muscle isolated from ?-actin/HcRed transgenic animals previously transplanted with either 1 x 106 unfractionated GFP  BM cells (A, B) or 100 GFP  c-kit Thy1.1loLin–Sca-1  HSCs (C). TA and TS muscles were injured by single intramuscular injection of cardiotoxin and examined for GFP  donor cell incorporation 5 weeks after injury. Serial sections were analyzed for colocalization of GFP (shown alone in the first column) with HcRed (second column) and the skeletal muscle marker -actinin (third column). Fluorescence images are electronically merged in the fourth column (green, GFP; red, HcRed; blue, anti--actinin); scale bar = 100 μm. GFP  myofibers were detected at an overall frequency of 0.1% (10 of 9,790) of myofibers in the injured TA of HSC-transplanted mice, 0.04% (8 of 19,328) of myofibers in the injured TA of BM-transplanted mice, and 0.1% (59 of 57,740) of myofibers in the injured TS of BM-transplanted mice. All GFP  myofibers detected in the injured muscles of BM-transplanted or HSC-transplanted mice coexpressed HcRed. Abbreviations: BM, bone marrow; GFP, green fluorescent protein; HSC, hematopoietic stem cell; TA, tibialis anterior; TS, triceps surae.

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We thank L. Jerabek for laboratory management; S. Smith for antibody preparation; A. Terskikh for provision of ?-actin/HcRed transgenic mice; L. Hidalgo, J. Dollaga, and D. Escoto for animal care; J. Mulholland for assistance with confocal microscopy; and I. Conboy and T. Rando for helpful discussions and critical reading of the manuscript. This work was supported in part through NIH grant CA86065 to I.L.W.; the VPUE Faculty Grant to R.I.S. and I.L.W.; NIH Training Grant in Molecular and Cellular Immunobiology, 5T32A I07290-16, to J.L.C.; American Cancer Society Grant PF-00-017-01-LBC to A.J.W.; and the Frederick Frank/Lehman Brothers, Inc.〞Irvington Institute Fellowship to A.J.W.6 w2 d/ `; \1 K3 P* \& ~, O2 z4 p

Richard I. Sherwood and Julie L. Christensen contributed equally to this work.6 {& V# E% v2 t/ l+ v

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